JP2010514768A - Compounds and pharmaceutical compositions for the treatment of viral infections - Google Patents

Abstract

Provided herein are compounds, compositions, and methods for the treatment of liver disorders including HCV and / or HBV infection. Specifically, nucleoside derivative compounds and compositions are disclosed, which can be administered alone or in combination with other antiviral agents.
[Selection] Figure 1

Description

(Cross-reference of related applications)
This patent application includes: 1) US provisional patent application 60 / 877,944 filed on December 28, 2006; 2) US provisional patent application 60 / 936,290 filed on June 18, 2007; and 3) Claims the benefit of priority over US Provisional Patent Application No. 60 / 985,891 filed on November 6, 2007. The disclosures of the above-mentioned applications are hereby incorporated by reference in their entirety.
(Field)
Provided herein are compounds, methods, and pharmaceutical compositions for use in the treatment of viral infections, including hepatitis C virus infection, and hepatitis B virus infection, in hosts in need thereof. In certain embodiments, phosphoramidate or phosphonoamidate nucleoside compounds capable of concentrating drugs in the liver are provided.

(background)
(Flaviviridae virus)
The Flaviviridae family of viruses includes at least three different genera: pestiviruses that cause disease in cattle and pigs; flaviviruses responsible for diseases such as dengue fever and yellow fever; and its only member is HCV Hepacivirus. The genus Flavivirus includes more than 68 members grouped on the basis of serological relevance (Calisher et al., J. Gen. Virol, 1993, 70, 37-43). Clinical symptoms are not uniform and include fever, encephalitis, and hemorrhagic fever (Fields Virology, editors: Fields, BN, Knipe, DM and Howley, PM, Lippincott-Raven Publishers, Philadelphia, PA 1996, Chapter 31, 931-959). Flaviviruses of global concern related to human disease include dengue hemorrhagic fever virus (DHF), yellow fever virus, shock syndrome, and Japanese encephalitis virus (Halstead, SB, Rev. Infect. Dis., 1984). 6, 251-264; Halstead, SB, Science, 239: 476-481, 1988; Monath, TP, New Eng. J. Med., 1988, 319, 641-643).

  The pestiviruses include bovine viral diarrhea virus (BVDV), classical swine fever virus (CSFV, also called swine cholera virus), and sheep border disease virus (BDV) (Moennig, V. et al., Adv. Vir. Res. 1992, 41, 53-98). Pestivirus infection of domesticated livestock (cattle, pigs and sheep) causes considerable economic losses worldwide. BVDV causes mucosal disease in cattle and is of great economic importance to the livestock industry (Meyers, G. and Thiel, HJ literature, Advances in Virus Research, 1996, 47, 53-118 Moennig V. et al., Adv. Vir. Res. 1992, 41, 53-98). Human pestiviruses are not as widely characterized as animal pestiviruses. However, serological studies show considerable pestivirus exposure in humans.

  Pestiviruses and hepaciviruses are closely related virus groups within the Flaviviridae family. Other closely related viruses in this family include GB virus A, GB virus A-like pathogens, GB virus-B, and GB virus-C (also called hepatitis G virus (HGV)). The hepacivirus group (hepatitis C virus; HCV) consists of a number of closely related, but genotypically distinguishable viruses that infect humans. There are approximately 6 HCV genotypes and more than 50 subtypes. Bovine viral diarrhea virus (BVDV) has been used as a surrogate to study HCV viruses, combined with the poor ability of hepaciviruses to grow efficiently in cell culture due to the similarity between pestiviruses and hepaciviruses. Often.

  The genetic composition of pestiviruses and hepaciviruses are very similar. These positive-strand RNA viruses have a single large open reading frame (ORF) that encodes all viral proteins required for viral replication. These proteins are expressed as polyproteins and are processed simultaneously and post-translationally by both cells and virally encoded proteinases to produce mature viral proteins. The viral protein responsible for replication of the viral genomic RNA is located approximately within the carboxy terminus. Two thirds of ORFs are named nonstructural (NS) proteins. The genetic composition and polyprotein processing of the nonstructural protein portion of the ORF of pestiviruses and hepaciviruses are very similar. For both pestiviruses and hepaciviruses, mature nonstructural (NS) proteins are expressed in the order from the amino terminus to the carboxy terminus of the ORF nonstructural protein coding region, p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B. Consists of.

  The pestivirus and hepacivirus NS proteins share sequence domains that are characteristic of specific protein functions. For example, the NS3 proteins of both groups of viruses have amino acid sequence motifs characteristic of serine proteinases and helicases (Gorbalenya et al. (1988) Nature 333: 22; Bazan and Fletterick (1989) Virology 171: 637-639; Gorbalenya et al. (1989) Nucleic Acid Res. 17.3889-3897). Similarly, pestivirus and hepacivirus NS5B proteins have motifs characteristic of RNA-specific RNA polymerases (Koonin, EV and Dolja, VV (1993) Crit. Rev. Biochem. Molec. Biol. 28: 375 -430).

  The actual roles and functions of the pestivirus and hepacivirus NS proteins in the viral life cycle are very similar. In either case, the NS3 serine proteinase is responsible for all proteolytic processing of the polyprotein precursor downstream of its position in the ORF (Wiskerchen and Collett (1991) Virology 184: 341-350; Bartenschlager et al. (1993) J. Virol. 67: 3835-3844; Eckart et al. (1993) Biochem. Biophys. Res. Comm. 192: 399-406; Grakoui et al. (1993) J. Virol. 67: 2832-2843. Grakoui et al. (1993) Proc. Natl. Acad. Sci. USA 90: 10583-10587; Hijikata et al. (1993) J. Virol. 67: 4665-4675; Tome et al. (1993) J. Virol; 67: 4017-4026). NS4A protein in each case acts as a cofactor with NS3 serine protease (Bartenschlager et al. (1994) J. Virol. 68: 5045-5055; Failla et al. (1994) J. Virol. 68: 3753-3760; Lin et al. (1994) 68: 8147-8157; Xu et al. (1997) J. Virol. 71:53 12-5322). NS3 protein of both viruses also functions as a helicase (Kim et al. (1995) Biochem. Biophys. Res. Comm. 215: 160-166; Jin and Peterson (1995) Arch. Biochem. Biophys. , 323: 47-53; Warrener and Collett (1995) J. Virol. 69: 1720-1726). Finally, pestivirus and hepacivirus NS5B proteins have the predicted RNA-specific RNA polymerase activity (Behrens et al. (1996) EMBOJ. 15: 12-22; Lchmann et al. (1997) J. Virol. 71: 8416-8428; Yuan (1997) Biochem. Biophys. Res. Comm. 232: 231-235; Hagedorn, PCT WO97 / 12033; US Pat. Nos. 5,981,247; 6,248,589, and 6,461,845 Zhong et al. (1998) J. Virol. 72.9365-9369).

(Hepatitis C virus)
Hepatitis C virus (HCV) is a major cause of chronic liver disease worldwide. (Boyer, N. et al., J. Hepatol. 32: 98-1 12, 2000). HCV grows slowly and causes viral infections and is a major cause of cirrhosis and liver cancer (Di Besceglie, AM and Bacon, BR, Scientific American, October: 80-85, (1999 ); Boyer, N. et al. J. Hepatol. 32: 98-112, 2000). Nearly 170,000,000 people are infected with HCV worldwide. (Boyer, N. et al., J. Hepatol. 32: 98-112, 2000). Cirrhosis caused by chronic hepatitis C infection causes 8,000 to 12,000 deaths per year in the United States, and HCV infection is a major indicator for liver transplantation.

  HCV is known to cause at least 80% of post-transfusion hepatitis and a significant proportion of sporadic acute hepatitis. Preliminary evidence also implicates HCV in many cases of "idiopathic" chronic hepatitis, "unknown" cirrhosis, and possibly other liver cancers unrelated to other hepatitis viruses such as hepatitis B virus (HBV) It is attached. A small number of healthy people appear to be chronic HCV carriers and vary with geographic and other epidemiological factors. The numbers will be substantially higher than for HBV, but the information is still preliminary; it is unclear how much of these people have asymptomatic chronic liver disease. (Merck Manual, ch. 69, p.901, 16th edition, (1992)).

  HCV is an outer membrane virus that contains an approximately 9.4 kb positive-sense single-stranded RNA genome. The viral genome consists of a 5 'untranslated region (UTR), a long open reading frame encoding a polyprotein precursor of approximately 3011 amino acids, and a short 3' UTR. The 5 ′ UTR is the most highly conserved part of the HCV genome and is important for the initiation and control of polyprotein translation. Translation of the HCV genome is initiated by a cap-independent mechanism known as intrasequence ribosome entry. This mechanism involves binding the ribosome to an RNA sequence known as an in-sequence ribosome entry site (IRES). The RNA pseudoknot structure has recently been determined to be an essential structural element of the HCV IRES. Viral structural proteins include the nucleocapsid core protein (C) and two envelope glycoproteins, E1 and E2. HCV also encodes two proteinases, a zinc-dependent metalloproteinase encoded by the NS2-NS3 region, and a serine proteinase encoded by the NS3 region. These proteinases are required to cleave specific regions of the precursor polyprotein into mature peptides. NS5B, the carboxyl half of nonstructural protein 5, contains an RNA-dependent RNA polymerase. The functions of the remaining nonstructural proteins, NS4A and NS4B, and NS5A (half of the amino terminus of nonstructural protein 5) are unknown.

  An important focus of current antiviral research is directed to the development of improved treatments for chronic HCV infection in humans (Di Besceglie, AM and Bacon, BR, Scientific American, October: 80-85, (1999)).

  Considering the fact that HCV infection has reached worldwide epidemic levels and has a tragic effect on infected patients, it is a new effective treatment for treating hepatitis C with low toxicity to the host. There remains a strong demand for providing new medicines.

  Furthermore, in view of the growing threat of other Flaviviridae infections, there remains a strong demand to provide new effective pharmaceuticals that have low toxicity to the host.

(Hepatitis B)
Hepatitis B virus has reached worldwide epidemic levels. After a 2-6 month incubation period in which the host is unaware of the infection, HBV infection can cause acute hepatitis and liver damage, which results in abdominal pain, jaundice, and increased blood concentrations of certain enzymes. HBV can develop fulminant hepatitis, a rapidly progressive and often fatal form of disease in which most compartments of the liver are destroyed. Patients typically recover from acute viral hepatitis. However, in some patients, high levels of viral antigens persist in the blood for long or indefinite periods, causing chronic infection. Chronic infection can cause chronic persistent hepatitis. Patients with chronic persistent HBV are most prevalent in developing countries. Chronic persistent hepatitis can cause fatigue, cirrhosis, and hepatocellular carcinoma, a primary liver cancer. In western industrialized countries, the high risk group for HBV infection includes HBV carriers or those who come into contact with their blood samples. The epidemiology of HBV is actually very similar to that of acquired immune deficiency syndrome, which explains why HBV infection is common among AIDS or infected patients associated with HIV . However, HBV is more infectious than HIV.

  Daily treatment with α-interferon, a genetically engineered protein, has shown promise. Human serum-derived vaccines have also been developed to immunize patients against HBV. The vaccine was prepared by genetic engineering. Vaccines have been found to be effective, but vaccine preparation is cumbersome due to the limited supply of human serum from chronic carriers and the lengthy and expensive purification procedures. In addition, each batch of vaccine prepared from different sera must be tested in chimpanzees to ensure safety. In addition, the vaccine cannot help patients already infected with the virus.

  An essential step in the mode of action of purines and pyrimidine nucleosides against viral diseases, particularly HBV and HCV, is their metabolic activation by cellular kinases, producing mono-, di- and triphosphate derivatives. The biologically active species of many nucleosides is the triphosphate form, which inhibits viral DNA polymerase, RNA polymerase, or reverse transcriptase or causes chain termination.

  Given the fact that hepatitis B and hepatitis C viruses have reached worldwide epidemic levels and have severe and many tragic effects on infected patients, they are less toxic to the host. There remains a strong demand to provide new and effective medicines for treating humans infected with the viruses they have.

  Accordingly, there remains a need for effective treatment of HCV and HBV infections.

(Summary)
Phosphoramidate and phosphonoamidate compounds of various therapeutic agents, and methods for their preparation, and use in the treatment of various disorders, including liver disorders, are provided. Such compounds can be used in some embodiments to allow concentration of the therapeutic agent in the liver. In one embodiment, the compound is S-pivaloyl-2-thioethyl phosphoramidate, S-pivaloyl-2-thioethylphosphonoamidate, S-hydroxypivaloyl-2-thioethyl phosphoramidate, or S-hydroxypivaloyl-2-thioethylphosphonoamidate.

  Various therapeutic phosphoramidate or phosphonoamidate compounds are provided. As used herein, “therapeutic phosphoramidate or phosphonoamidate compound” includes a therapeutic agent derivatized to contain a phosphoramidate or phosphonoamidate group. The therapeutic agent is, for example, an antiviral agent that includes or is derivatized to include a reactive group such as hydroxyl for attachment of a phosphoramidate or phosphonoamidate moiety. Such therapeutic agents include, but are not limited to, nucleosides and nucleoside analogs including acyclic nucleosides. In some embodiments, phosphoramidates of nucleotides and nucleotide analogs are also provided, such as 1 ', 2', 3 'branched, and 4' branched nucleoside phosphoramidates. Such compounds can be administered in an effective amount for the treatment of liver disorders such as hepatitis B, including the resistant strain, and infections including hepatitis C infection.

  In certain embodiments, but not limited to any theory, the parent drug can be obtained by selective metabolism of phosphoramidate or phosphonoamidate compounds in the liver, thus accumulating the parent drug in the host's liver. be able to. By selectively targeting and activating compounds in the liver, the distribution of active compounds in the gastrointestinal tract that is potentially undesirable can be reduced. Moreover, the therapeutic amount of the active compound at the site of infection in the liver can be increased.

  In certain embodiments, the 5′-monophosphate or phosphonate of the parent nucleoside (or nucleoside derivative) drug is formed by metabolism of a phosphoramidate or phosphonoamidate compound in the liver, and the monophosphate or phosphonate is It can form and accumulate in the liver. Thus, in certain embodiments, the phosphoramidate effectively provides a phosphate that is stabilized on a nucleoside or nucleoside analog. In certain embodiments, if the compound needs to be triphosphorylated to become active, this advantageously eliminates the need for an initial phosphorylation step, rather than an active triphosphate that inhibits the target enzyme. Rapid formation can be promoted and the overall activity of the nucleoside or nucleoside analog can be enhanced.

  Without being limited to any theory, in one embodiment, a phosphoramidate of a nucleoside, such as a 2′-C-methyl-ribonucleoside, is provided, which is selectively enriched in the liver after oral administration, wherein hepatocytes Can be metabolized to produce 5′-monophosphate, which can be enzymatically converted to an active form of 5′-triphosphate that inhibits HCV polymerase. Thus, the potential therapeutic dose can be reduced compared to administering the nucleoside parent molecule.

  Thus, in some embodiments, following oral administration of the phosphoramidate and phosphonoamidate compounds described herein, the compound is conveniently concentrated in the hepatocytes at the site of infection and the phosphate or phosphonate in the hepatocytes. Which can then optionally be further phosphorylated to exert its therapeutic effect.

  By these methods, the phosphoramidate or phosphonoamidate compound disclosed in the present specification can be accumulated in the liver of the host, so that the method described in this specification can be applied to, for example, hepatitis B or hepatitis C. May be useful for the treatment and / or prevention of liver diseases or disorders.

  In certain embodiments, a compound provided herein is a flaviviridae infection, as well as anti-flaviviridae antibody positive and flaviviridae positive status, chronic liver inflammation caused by HCV, cirrhosis, fibrosis, acute Useful for the prevention and treatment of hepatitis, fulminant hepatitis, chronic persistent hepatitis, and other related conditions such as fatigue. These compounds, or formulations, may also be used to prevent or delay the progression of clinical disease in individuals who are positive for or exposed to anti-Flavaviviridae antibodies, or Flaviviridae antigens. Can be used prophylactically. In one specific embodiment, the Flaviviridae is hepatitis C. In certain embodiments, the compounds are used to treat any virus that replicates via an RNA-dependent RNA polymerase.

  Also comprising administering an effective amount of a compound provided herein, either alone or optionally in a pharmaceutically acceptable carrier, either in combination with another anti-flaviviridae or alternately. A method for the treatment of Flaviviridae infections in a host, including a human, is provided.

  In certain embodiments, hepatitis B infection and other anti-HBV antibody positive and HBV positive conditions, chronic liver inflammation caused by HBV, fibrosis, cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis, and fatigue Provided herein are methods for the treatment and / or prevention of a related condition.

  In certain embodiments, various pharmaceutical phosphoramidate or phosphonoamidate compounds are prepared and used therapeutically as described herein to enhance delivery of drugs to the liver. be able to. In one embodiment, the compound is S-acyl-2-thioethyl phosphoramidate, or an S-acyl-2-thioethylphosphonoamidate derivative, such as S-pivaloyl-2-thioethyl phosphoramidate, or S-hydroxypivaloyl-2-thioethylphosphonoamidate derivative.

又はその医薬として許容し得る塩、溶媒和物、立体異性形態、互変異性形態、若しくは多形形態であり、式中、
X^aは、

であり、
Zは、O、又はSであり；
それぞれのWは、独立してO、又はSであり；
R^y、及びR^uは、それぞれ独立して、全て任意に置換された、アルキル、アルケニル、アルキニル、アリール、アリールアルキル、シクロアルキル、シクロアルケニル、アミノ、アミノアルキル、ヒドロキシアルキル、アルコキシ、ヘテロシクリル、又はヘテロアリールを表し；
R^a、及びR^bは、以下の通りに選択され：
i）R^a、及びR^bは、それぞれ独立して、全て任意に置換された、水素、アルキル、カルボキシアルキル、ヒドロキシアルキル、ヒドロキシアリールアルキル、アシルオキシアルキル、アミノカルボニルアルキル、アルコキシカルボニルアルキル、アリール、アリールアルキル、シクロアルキル、アリール、ヘテロアリール、若しくはヘテロシクリルであるか；又は
ii）R^a、及びR^bは、これらが置換される窒素原子と共に3〜7員の複素環若しくはヘテロアリール環を形成し；
nは、0〜3であり；n₂は、1〜4であり；かつ、
R¹は、抗ウイルス薬のヒドロキシ基からの水素の除去によって誘導体化できる部分である。 The phosphoramidate or phosphonoamidate compounds provided herein, and salts thereof, and compositions comprising the compounds are useful for the treatment of liver disorders such as HBV and / or HCV infection. . In one embodiment, a compound provided herein is a compound of formula I:

Or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form or polymorphic form thereof, wherein
X ^a is

And
Z is O or S;
Each W is independently O or S;
R ^y and R ^u are each independently an optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, amino, aminoalkyl, hydroxyalkyl, alkoxy, heterocyclyl, or Represents heteroaryl;
R ^a and R ^b are selected as follows:
i) R ^a and R ^b are each independently optionally substituted hydrogen, alkyl, carboxyalkyl, hydroxyalkyl, hydroxyarylalkyl, acyloxyalkyl, aminocarbonylalkyl, alkoxycarbonylalkyl, aryl, aryl Is alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; or
ii) R ^a and R ^b together with the nitrogen atom to which they are substituted form a 3-7 membered heterocyclic or heteroaryl ring;
n is 0 to 3; n ₂ is an 1-4; and,
R ¹ is a moiety that can be derivatized by removal of hydrogen from the hydroxy group of the antiviral drug.

であり、
Zは、O、S、NH、又はNR^Wであり、式中R^Wは、例えば全て任意に置換された、アルキル、アルキル、アルケニル、アルキニル、アリール、アリールアルキル、シクロアルキル、シクロアルケニル、アミノ、アミノアルキル、アルコキシ、ヘテロシクリル、又はヘテロアリールであり；
それぞれのWは、O、S、NH、又はNR^Wであり、式中R^Wは、例えば全て任意に置換された、アルキル、アルキル、アルケニル、アルキニル、アリール、アリールアルキル、シクロアルキル、シクロアルケニル、アミノ、アミノアルキル、アルコキシ、ヘテロシクリル、又はヘテロアリールであり；
R^y、及びR^uは、それぞれ独立して、全て任意に置換された、アルキル、アルケニル、アルキニル、アリール、アリールアルキル、シクロアルキル、シクロアルケニル、アミノ、アミノアルキル、アルコキシ、ヘテロシクリル、又はヘテロアリールを表し；
R^a、及びR^bは、以下の通りに選択され：
i）R^a、及びR^bは、それぞれ独立して、全て任意に置換された、水素、アルキル、カルボキシアルキル、ヒドロキシアルキル、ヒドロキシアリールアルキル、アシルオキシアルキル、アミノカルボニルアルキル、アルコキシカルボニルアルキル、アリール、アリールアルキル、シクロアルキル、ヘテロアリール、若しくはヘテロシクリルであるか；又は、
ii）R^a、及びR^bは、これらが置換される窒素原子と共に3〜7員の複素環若しくはヘテロアリール環を形成し；
nは、0〜3であり；n₂は、1〜4であり；かつ、
R¹は、本明細書に記載したとおりである。 In another embodiment,
X ^a is

And
Z is, O, a S, NH, or NR ^W, wherein R ^W is for example substituted all optionally alkyl, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, amino, Aminoalkyl, alkoxy, heterocyclyl, or heteroaryl;
Each W is, O, a S, NH, or NR ^W, wherein R ^W is, for example all optionally substituted, alkyl, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, Is amino, aminoalkyl, alkoxy, heterocyclyl, or heteroaryl;
R ^y and R ^u are each independently an optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, amino, aminoalkyl, alkoxy, heterocyclyl, or heteroaryl. Representation;
R ^a and R ^b are selected as follows:
i) R ^a and R ^b are each independently optionally substituted hydrogen, alkyl, carboxyalkyl, hydroxyalkyl, hydroxyarylalkyl, acyloxyalkyl, aminocarbonylalkyl, alkoxycarbonylalkyl, aryl, aryl Is alkyl, cycloalkyl, heteroaryl, or heterocyclyl; or
ii) R ^a and R ^b together with the nitrogen atom to which they are substituted form a 3-7 membered heterocyclic or heteroaryl ring;
n is 0 to 3; n ₂ is an 1-4; and,
R ¹ is as described herein.

One skilled in the art will recognize that compounds of formula I can be designed or prepared, for example, via condensation or dehydration, for example by reaction at the hydroxy group of the antiviral agent. For convenience, in the description herein, when identifying a substituent such as the exemplary R ¹ group as a drug, those skilled in the art will recognize, for example, compounds of formula I such as antiviral drug radicals and the like. It will be appreciated that the derivatives include: These derivatives can be prepared, for example, in a dehydration reaction, for example by removal of hydrogen radicals from the hydroxy group of the drug. Where appropriate, certain derivatives can be prepared to produce compounds of Formula I by modification of antiviral phosphates or phosphonates.

In certain embodiments of formula I, R ¹ is a nucleoside comprising a cyclic or acyclic sugar, or an analogue thereof.

In certain embodiments, R ¹ is an HCV virus selected from ribavirin, viramidine, 2′-C-methylcytidine, 2′-C-methylguanosine, baropicitabine (NM 283), MK-0608, and PSI-6130 Antiviral nucleoside analogues useful for the treatment of infection.

In certain embodiments, R ¹ is lamivudine (Epivir-HBV, Zeffix, or Heptodin), adefovir, entecavir (Baraclude), terbivudine (Tyzeka, Sebivo) , Emtricitabine (FTC), clevudine (L-FMAU), viread (tenofovir), torcitabine, valtorcitabine (monoval LdC), amdoxovir (DAPD), and RCV (Racivir) Is an antiviral nucleoside analog useful for the treatment of HBV viral infections selected from:

In certain embodiments, R ¹ is a non-nucleoside antiviral agent useful for the treatment of an HBV viral infection selected from resiquimod, or celgosivir.

In certain embodiments according to Formula I, R ^y is substituted alkyl, such as hydroxyalkyl or aminoalkyl; and R ^a and R ^b are each independently hydrogen, alkyl, substituted Alkyl, benzyl, or substituted benzyl such as hydroxy-substituted or amino-substituted alkyl or benzyl. In another embodiment, R ^y is —OR ^c , —C (R ^c ) ₃ , or NHR ^c —, wherein each R ^c is independently alkyl, substituted alkyl, aryl, or Substituted aryl, such as hydroxy-substituted or amino-substituted alkyl or aryl; and R ^a and R ^b are independently hydrogen, alkyl, substituted alkyl, benzyl, or substituted benzyl, such as Hydroxy- or amino-substituted alkyl or benzyl. In a further embodiment, R ^a and R ^b are independently benzyl, or substituted alkyl. In a further embodiment, R ^y is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, R ^y is —C (CH ₃ ) ₂ CH ₂ OH.

In certain embodiments, the compounds provided herein are selected such that R ¹ is not 3′-azido-2 ′, 3′-dideoxythymidine.

又はその医薬として許容し得る塩、溶媒和物、立体異性形態、互変異性形態、若しくは多形形態であり、式中、
R^yは、全て任意に置換された、アルキル、アルケニル、アルキニル、アリール、アリールアルキル、シクロアルキル、シクロアルケニル、アミノ、アミノアルキル、ヒドロキシアルキル、ヘテロシクリル、又はヘテロアリールであり；
R^a、及びR^bは、以下の通りに選択され：
i）R^a、及びR^bは、それぞれ独立して、全て任意に置換された、水素、アルキル、カルボキシアルキル、ヒドロキシアルキル、ヒドロキシアリールアルキル、アシルオキシアルキル、アミノカルボニルアルキル、アルコキシカルボニルアルキル、アリール、アリールアルキル、シクロアルキル、アリール、ヘテロアリール、若しくはヘテロシクリルであるか；又は、
ii）R^a、及びR^bは、これらが置換される窒素原子と共に3〜7員の複素環、又はヘテロアリール環を形成し；かつ、
R¹は、ヌクレオシド又はヌクレオシド類似体などの抗ウイルス剤である（本明細書に使用される、R¹が抗ウイルス剤である場合は、その実施態様には、抗ウイルス薬のヒドロキシ基からの水素の除去によって誘導体化できる部分を含む）。 In another embodiment, a compound provided herein is a compound of formula IIa or IIb:

Or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form or polymorphic form thereof, wherein
R ^y is all optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, amino, aminoalkyl, hydroxyalkyl, heterocyclyl, or heteroaryl;
R ^a and R ^b are selected as follows:
i) R ^a and R ^b are each independently optionally substituted hydrogen, alkyl, carboxyalkyl, hydroxyalkyl, hydroxyarylalkyl, acyloxyalkyl, aminocarbonylalkyl, alkoxycarbonylalkyl, aryl, aryl Is alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; or
ii) R ^a and R ^b together with the nitrogen atom to which they are substituted form a 3-7 membered heterocycle or heteroaryl ring; and
R ¹ is an antiviral agent, such as a nucleoside or nucleoside analog (as used herein, when R ¹ is an antiviral agent, embodiments include from the hydroxy group of the antiviral agent Including moieties that can be derivatized by removal of hydrogen).

In certain embodiments according to formula IIa or IIb, R ^y is a substituted alkyl, such as hydroxyalkyl or aminoalkyl; and R ^a and R ^b are independently hydrogen, alkyl, Substituted alkyl, benzyl, or substituted benzyl, such as hydroxy- or amino-substituted alkyl or benzyl. In another embodiment, R ^y is -OR ^c , -C (R ^c ) ₃ , or -NHR ^c , wherein each R ^c is independently alkyl, substituted alkyl, aryl, or Substituted aryl, such as hydroxy-substituted or amino-substituted alkyl or aryl; and R ^a and R ^b are independently hydrogen, alkyl, substituted alkyl, benzyl, or substituted benzyl, such as Hydroxy- or amino-substituted alkyl or benzyl. In a further embodiment, R ^a and R ^b are independently benzyl, or substituted alkyl. In a further embodiment, R ^y is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, R ^y is —C (CH ₃ ) ₂ CH ₂ OH.

の化合物であり、
式中、R^a、R^b、及びR^yは、式Iに記載したとおりであり、かつ
式中、R²、及びR³は、それぞれ独立してH、直鎖、分枝、又は環状のアルキル；アシル（低級アシルを含む）；CO-アルキル、CO-アリール、CO-アルコキシアルキル、CO-アリールオキシアルキル、CO-置換されたアリール、メタンスルホニルを含むアルキルスルホニル、又はアリールアルキルスルホニルなどのスルホナートエステル、及びベンジルであって、式中フェニル基は、任意に置換されており；アルキルスルホニル、アリールスルホニル、アリールアルキルスルホニル、リン脂質などの脂質；アミノ酸；及びアミノ酸残基、炭水化物；ペプチド；コレステロール；例えば、インビボで投与されたときに、式中R²、及び／又はR³が独立してHである化合物を提供することができるその他の医薬として許容し得る脱離基か；又はR²、及びR³は、アルキル、エステル、又はカルバメート結合によって環状基を形成するように連結され；かつ、それぞれのR^Lは、独立してH、カルバミル、直鎖、分枝、又は環状のアルキル；アシル（低級アシルを含む）；CO-アルキル、CO-アリール、CO-アルコキシアルキル、CO-アリールオキシアルキル、CO-置換されたアリール、メタンスルホニルを含むアルキルスルホニル若しくはアリールアルキルスルホニルなどのスルホナートエステル、及びベンジルであって、式中フェニル基は、任意に置換されており；アルキルスルホニル、アリールスルホニル、アリールアルキルスルホニル、リン脂質などの脂質；アミノ酸；アミノ酸残基；又は炭水化物である。このパラグラフに従った特定の実施態様において、R²、及びRは、それぞれHであり；R^yは、置換されたアルキル、例えばヒドロキシアルキル、又はアミノアルキルであり；かつ、R^a、及びR^bは、独立して水素、アルキル、置換されたアルキル、ベンジル、又は置換されたベンジル、例えばヒドロキシ置換若しくはアミノ置換されたアルキル又はベンジルである。別の実施態様において、R²、及びR³は、それぞれHであり；R^yは、-OR^c、-C(R^c)₃、又は-NHR^cであり、式中それぞれのR^cは、独立してアルキル、置換されたアルキル、アリール、又は置換されたアリール、例えばヒドロキシ置換若しくはアミノ置換されたアルキル又はアリールであり；かつR^a、及びR^bは、独立して水素、アルキル、置換されたアルキル、ベンジル、又は置換されたベンジル、例えばヒドロキシ置換若しくはアミノ置換されたアルキル又はベンジルである。さらなる実施態様において、R²、及びR³は、それぞれHであり；R^a、及びR^bは、独立してベンジル、又は置換されたアルキルである。さらなる実施態様において、R²、及びR³は、それぞれHであり；R^yは、アルキル、及びヒドロキシアルキルからなる群から選択される。特定の実施態様において、R²、及びR³は、それぞれHであり；R^yは、-C(CH₃)₂CH₂OHである。このパラグラフに従った特定の実施態様において、R²、及びR³は、それぞれ水素であり、R^aは、水素であり、R^bは、-CH₂-C₆H₅であり、かつR^yは、-C(CH₃)₂CH₂OHである。 In another embodiment, the compounds provided herein have the formula:

A compound of
Wherein R ^a , R ^b , and R ^y are as described in formula I, and wherein R ² and R ³ are each independently H, linear, branched, or cyclic Alkyl; acyl (including lower acyl); sulfo such as CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl including methanesulfonyl, or arylalkylsulfonyl Nert esters, and benzyl, wherein the phenyl group is optionally substituted; lipids such as alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, phospholipids; amino acids; and amino acid residues, carbohydrates; peptides; cholesterol ; for example, can provide when administered in vivo, the compounds wherein R ^2, and / or R ³ is independently H If other pharmaceutically acceptable leaving group; or R ^2, and R ^3, alkyl, ester, or linked so as to form a cyclic group by a carbamate bond; and each of R ^L is independently H, carbamyl, linear, branched, or cyclic alkyl; acyl (including lower acyl); CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, Sulfonate esters such as alkylsulfonyl or arylalkylsulfonyl, including methanesulfonyl, and benzyl, wherein the phenyl group is optionally substituted; lipids such as alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, phospholipids Amino acids; amino acid residues; or carbohydrates. In certain embodiments according to this paragraph, R ^2, and R is H, respectively; R ^y is substituted alkyl, e.g. hydroxyalkyl, or aminoalkyl; and, R ^a, and R ^b Are independently hydrogen, alkyl, substituted alkyl, benzyl, or substituted benzyl, such as hydroxy- or amino-substituted alkyl or benzyl. In another embodiment, R ² and R ³ are each H; R ^y is —OR ^c , —C (R ^c ) ₃ , or —NHR ^c , wherein each R ^c is Independently alkyl, substituted alkyl, aryl, or substituted aryl, such as hydroxy-substituted or amino-substituted alkyl or aryl; and R ^a and R ^b are independently hydrogen, alkyl, substituted Alkyl, benzyl, or substituted benzyl, such as hydroxy- or amino-substituted alkyl or benzyl. In a further embodiment, R ² and R ³ are each H; R ^a and R ^b are independently benzyl, or substituted alkyl. In a further embodiment, R ² and R ³ are each H; R ^y is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, R ² and R ³ are each H; R ^y is —C (CH ₃ ) ₂ CH ₂ OH. In certain embodiments according to this paragraph, R ² and R ³ are each hydrogen, R ^a is hydrogen, R ^b is —CH ₂ —C ₆ H ₅ , and R ^y Is —C (CH ₃ ) ₂ CH ₂ OH.

の化合物であり、
式中、R^a、R^b、及びR^yは、式Iに記載したとおりである。R^dは、水素、アルキル、及びアルコキシからなる群から選択される。特定の実施態様において、R^dは、水素、メチル、又はメトキシである。このパラグラフに従った特定の実施態様において、R^yは、置換されたアルキル、例えばヒドロキシアルキル、又はアミノアルキルであり；かつ、R^a、及びR^bは、独立して水素、アルキル、置換されたアルキル、ベンジル、又は置換されたベンジル、例えばヒドロキシ置換若しくはアミノ置換されたアルキル又はベンジルである。別の実施態様において、R^yは、-OR^c、-C(R^c)₃、又は-NHR^cであり、式中それぞれのR^cは、独立してアルキル、置換されたアルキル、アリール、又は置換されたアリール、例えばヒドロキシ置換若しくはアミノ置換されたアルキル又はアリールであり；かつ、R^a、及びR^bは、独立して水素、アルキル、置換されたアルキル、ベンジル、又は置換されたベンジル、例えばヒドロキシ置換若しくはアミノ置換されたアルキル又はベンジルである。さらなる実施態様において、R^a、及びR^bは、独立してベンジル、又は置換されたアルキルである。さらなる実施態様において、R^yは、アルキル、及びヒドロキシアルキルからなる群から選択される。特定の実施態様において、R^yは、-C(CH₃)₂CH₂OHである。このパラグラフに従った特定の実施態様において、R²、及びR³は、それぞれ水素であり、R^aは、水素であり、R^bは、-CH₂-C₆H₅であり、かつR^yは、-C(CH₃)₂CH₂OHである。このパラグラフに従った特定の実施態様において、R^aは、水素であり、R^bは、-CH₂-C₆H₅であり、かつR^yは、-C(CH₃)₂CH₂OHである。 In another embodiment, the compounds provided herein have the formula:

A compound of
In the formula, R ^a , R ^b , and R ^y are as described in formula I. R ^d is selected from the group consisting of hydrogen, alkyl, and alkoxy. In certain embodiments, R ^d is hydrogen, methyl, or methoxy. In certain embodiments according to this paragraph, R ^y is substituted alkyl, such as hydroxyalkyl or aminoalkyl; and R ^a and R ^b are independently hydrogen, alkyl, substituted Alkyl, benzyl, or substituted benzyl, such as hydroxy-substituted or amino-substituted alkyl or benzyl. In another embodiment, R ^y is -OR ^c , -C (R ^c ) ₃ , or -NHR ^c , wherein each R ^c is independently alkyl, substituted alkyl, aryl, or Substituted aryl, such as hydroxy-substituted or amino-substituted alkyl or aryl; and R ^a and R ^b are independently hydrogen, alkyl, substituted alkyl, benzyl, or substituted benzyl, such as Hydroxy- or amino-substituted alkyl or benzyl. In a further embodiment, R ^a and R ^b are independently benzyl, or substituted alkyl. In a further embodiment, R ^y is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, R ^y is —C (CH ₃ ) ₂ CH ₂ OH. In certain embodiments according to this paragraph, R ² and R ³ are each hydrogen, R ^a is hydrogen, R ^b is —CH ₂ —C ₆ H ₅ , and R ^y Is —C (CH ₃ ) ₂ CH ₂ OH. In certain embodiments according to this paragraph, R ^a is hydrogen, R ^b is —CH ₂ —C ₆ H ₅ , and R ^y is —C (CH ₃ ) ₂ CH ₂ OH is there.

を含む。 In one embodiment, for example, a nucleoside that can be derivatized to include a phosphoramidate or phosphonoamidate at the 5 ′ position:

including.

を含む。 Examples of phosphoramidate or phosphonoamidate nucleoside compounds include

including.

を含む。 In one embodiment, for example, a nucleoside that can be derivatized to include a phosphoramidate or phosphonoamidate at the 5 ′ position:

including.

を含む。 In one embodiment, the phosphoramidate or phosphonoamidate nucleoside compound includes:

including.

を含む。 In one embodiment, for example, a nucleoside that can be derivatized to include a phosphoramidate or phosphonoamidate at the 5 ′ position:

including.

を含む。 In one embodiment, the phosphoramidate or phosphonoamidate nucleoside compound is:

including.

  In one embodiment, the compounds described herein are provided or administered in combination with a second therapeutic agent, such as those useful for the treatment or prevention of HBV and / or HCV infection. Exemplary therapeutic agents are described in detail in the following sections.

  In another embodiment, for example, a therapeutically or prophylactically effective amount of a compound described herein of formula I, IIa, or IIb and one useful for the treatment or prevention of HBV and / or HCV infection, etc. A pharmaceutical composition, single unit dosage form suitable for use in treating or preventing disorders such as HBV and / or HCV infection, comprising a therapeutically or prophylactically effective amount of a second therapeutic agent And kits are provided.

  In certain embodiments, there is provided a method of treating liver disorders comprising administering to an individual in need thereof a therapeutically effective amount of a nucleoside or nucleoside analog phosphoramidate or phosphonoamidate derivative, optionally comprising The derivative is S-pivaloyl-2-thioethyl phosphoramidate or S-pivaloyl-2-thioethylphosphonoamidate derivative. Derivatives are arbitrarily selected from the compounds disclosed herein.

In some embodiments, the following are provided herein:
(A) a compound as described herein, eg, of Formula I, IIa, or IIb, and pharmaceutically acceptable salts and compositions thereof;
(B) Used for the treatment and / or prevention of liver disorders, including flaviviridae infections, especially in individuals diagnosed with flaviviridae infection or at risk of becoming infected with hepatitis C For example, compounds as described herein of formula I, IIa, or IIb, and pharmaceutically acceptable salts and compositions thereof;
(C) a method for the preparation of a compound as described herein for example of formula I, IIa, or IIb, as described in more detail below;
(D) a pharmaceutical formulation comprising a compound as described herein of formula I, IIa, or IIb, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent;
(E) a compound as described herein, eg, of Formula I, IIa, or IIb, optionally in a pharmaceutically acceptable carrier or diluent, along with one or more other effective anti-HCV agents, or A pharmaceutical formulation comprising a pharmaceutically acceptable salt thereof;
(F) Treatment of a host infected with Flaviviridae, comprising administration of an effective amount of a compound, pharmaceutically acceptable salt, or composition thereof as described herein, eg, of Formula I, IIa, or IIb And / or methods for prevention;
(G) in combination with and / or alternately with one or more active anti-HCV agents, eg, a compound as described herein of formula I, IIa, or IIb, a pharmaceutically acceptable salt thereof, or A method for the treatment and / or prevention of a host infected with Flaviviridae, comprising administration of an effective amount of the composition;
(H) for use in the treatment and / or prevention of HBV infection, particularly in individuals diagnosed with HBV infection or at risk of becoming infected with hepatitis B, eg Or a compound of IIb as described herein, and pharmaceutically acceptable salts and compositions thereof;
(I) a compound as described herein of formula I, IIa, or IIb, optionally in a pharmaceutically acceptable carrier or diluent, along with one or more other effective anti-HBV agents, or A pharmaceutical formulation comprising a pharmaceutically acceptable salt thereof;
(J) hepatitis B infection, including administering an effective amount of a compound of formula I, IIa, or IIb, or a pharmaceutically acceptable salt or composition thereof, as described herein, And methods for the treatment and / or prevention of anti-HBV antibody positive and HBV positive conditions, chronic liver inflammation caused by HBV, cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis, and fatigue .
(K) A prophylactic method for preventing or delaying the progression of clinical disease in an individual who is positive for or exposed to anti-HBV antibody or HBV antigen.

  Flaviviridae that can be treated is generally discussed in, for example, Fields Virology, Editors: Fields, BN, Knipe, DM and Howley, PM, Lippincott-Raven Publishers, Philadelphia, PA, Chapter 31, 1996. Has been. In certain embodiments of the invention, the Flaviviridae is HCV. In an alternative embodiment, the Flaviviridae is a flavivirus or pestivirus. Specific flaviviruses include, but are not limited to: Absettarov, Alfuy, Apoi, Aroa, Bagaza, Banzi, Bouboui , Bussuquara, Cacipacore, Cray Island, Dakar bat, Dengue 1, Dengue 2, Dengue 3, Dengue 4 ), Edge Hill, Entebbe bat, Gadgets Gully, Hanzalova, Hypr, Ilheus, Israel turkey meningoencephalitis, Japan Encephalitis (Japanese encephalitis), Jugra, Jutiapa, Kadam, Karshi, Kedougou, Ko Kokobera, Koutango, Kumlinge, Kunjin, Kyasanur Forest disease, Langat, Jumping disease, Meaban, Modoc ), Montana myotis leukoencephalitis, Murray valley encephalitis, Naranjal, Negishi, Ntaya, Omsk hemorrhagic fever, Phnom Penhbat Phnom-Penh bat, Powassan, Rio Bravo, Rocio, Royal Farm, Russian spring-summer encephalitis, Saboya, St. Louis encephalitis ( St. Louis encephalitis, Sal Vieja San Perlita, San Perlita, Saumarez Reef , Sepik, Sokuluk, Spondweni, Stratford, Tembusu, Tyuleniy, Uganda S, Usutu, Wesselsbron West Nile, Yaounde, Yellow fever, and Zika.

  Pestiviruses that can be treated are generally discussed in Fields Virology, Editors: Fields, BN, Knipe, DM and Howley, PM, Lippincott-Raven Publishers, Philadelphia, PA, Chapter 33, 1996. . Specific pestiviruses include, but are not limited to: bovine viral diarrhea virus (“BVDV”), classic swine fever virus (“CSFV”, also called swine cholera virus), and border disease virus (“BDV”). ").

FIG. 5 shows depletion of NM108 hydroxy SATE phosphoramidate (B299) after incubation with and without NADPH in monkey liver S9.

FIG. 5 shows depletion of NM107 hydroxy SATE phosphoramidate (B102) after incubation with and without NADPH in monkey liver S9.

(Description of exemplary embodiments)
Provided herein are compounds, compositions and methods useful for treating liver disorders such as HBV and / or HCV infection in a subject. Further useful dosage forms for such methods are provided.

(Definition)
When referring to the compounds provided herein, the following terms have the following meanings unless otherwise indicated.

As used herein, the term “alkyl” is typically C ₁ -C ₁₀ saturated, linear, branched, or cyclic, primary, secondary, or tertiary unless otherwise specified. Contains hydrocarbons, in particular methyl, CF ₃ , CCl ₃ , CFCl ₂ , CF ₂ Cl, ethyl, CH ₂ CF ₃ , CF ₂ CF ₃ , propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec butyl, t- Includes butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl. The term includes both substituted and unsubstituted alkyl groups, particularly halogenated alkyl groups, and more particularly further fluorinated alkyl groups. Non-limiting examples of moieties that can be substituted for alkyl groups include those known to those skilled in the art, such as Greene et al., Protective Groups in Organic Synthesis, incorporated herein by reference. Organic Synthesis), John Wiley and Sons, 2nd edition, 1991, halogenated (fluoro, chloro, bromo, or iodo, either unprotected or protected as required) ), Hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate.

The term “lower alkyl” as used herein, unless otherwise stated, includes C ₁ -C ₄ saturated straight, branched, or, where appropriate, cyclic (including substituted and unsubstituted moieties) For example, an alkyl group of cyclopropyl).

“Alkylene” includes divalent aliphatic saturated hydrocarbon groups, which may be straight or branched, in particular having up to about 11 carbon atoms, and more particularly having 1 to 6 carbon atoms. The term includes methylene (—CH ₂ —), ethylene (—CH ₂ CH ₂ —), propylene isomers (eg, —CH ₂ CH ₂ CH ₂ —, and —CH (CH ₃ ) CH ₂ —) and others. Illustrated by the group of

“Alkenyl”, in certain embodiments, is straight-chain or branched and can have at least one, or one to two sites of olefinic unsaturation, up to about 11 carbon atoms, up to 2 Includes monovalent olefinically unsaturated hydrocarbon groups having up to ˜8 carbon atoms, or 2 to 6 carbon atoms. Exemplary alkenyl groups include ethenyl (—CH═CH ₂ ), n-propenyl (—CH ₂ CH═CH ₂ ), isopropenyl (—C (CH ₃ ) ═CH ₂ ), vinyl, and substituted vinyl, Including others.

“Alkenylene”, in certain embodiments, is linear or branched and can have at least one, or 1-2 sites of olefinic unsaturation, up to about 11 carbon atoms, or Contains divalent olefinically unsaturated hydrocarbon groups having 2 to 6 carbon atoms. The term includes ethenylene (—CH═CH—), propenylene isomers (eg, —CH═CHCH ₂ —, and —C (CH ₃ ) ═CH—, and —CH═C (CH ₃ )), etc. Illustrated by the group.

“Alkynyl”, in certain embodiments, is linear or branched and can have at least one, or one to two sites of alkynyl unsaturation, up to about 11 carbon atoms, or Contains acetylenically unsaturated hydrocarbon groups having 2 to 6 carbon atoms. Non-limiting examples of alkynyl groups include acetylene, ethynyl (—C≡BCH), propargyl (—CH ₂ C≡CH), and others.

  The term “aryl” as used herein includes phenyl, biphenyl, or naphthyl, and preferably phenyl, unless otherwise specified. The term includes substituted and unsubstituted moieties. Aryl groups are known to those skilled in the art, for example, in Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons Second Edition, 1991, which is incorporated herein by reference. As taught, halogen (fluoro, chloro, bromo, or iodo), alkyl, haloalkyl, hydroxyl, amino, alkylamino, aryl, either unprotected or protected as required Substituted with any described moiety, including but not limited to one or more moieties selected from the group consisting of amino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate can do.

  “Alkoxy” includes —OR groups where R is alkyl. Specific alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy and others.

  “Alkoxycarbonyl” includes a radical —C (O) -alkoxy where alkoxy is as defined herein.

“Amino” includes the radical —NH ₂ .

  “Carboxyl” includes the radical —C (O) OH.

  The term “alkylamino” or “arylamino” includes amino groups having one or two alkyl or aryl substituents, respectively. Unless otherwise specifically indicated in this application, lower alkyl is preferred when alkyl is a suitable moiety. Similarly, when alkyl or lower alkyl is a suitable moiety, unsubstituted alkyl or lower alkyl is preferred.

  “Halogen” or “halo” includes chloro, bromo, fluoro, or iodo.

  “Monoalkylamino” includes the group alkyl-NR′—, wherein R ′ is selected from hydrogen and alkyl.

  “Thioalkoxy” includes the group —SR where R is alkyl.

  The term “protected” as used herein, unless otherwise defined, refers to a group appended to an oxygen, nitrogen, or phosphorus atom to prevent further reaction or for other purposes. Say. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis.

  “Pharmaceutically acceptable salt” refers to a compound provided herein that retains its biological properties and is not toxic or otherwise undesirable for pharmaceutical use. Contains any salt. Such salts may be derived from various organic and inorganic counter ions well known in the art. Such salts include: (1) hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, Glycolic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid , Picric acid, cinnamic acid, mandelic acid, phthalic acid, lauric acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] -oct-2-ene-1- Ruboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfamic acid, quinic acid, muconic acid Acid addition salts formed with organic acids or inorganic acids such as, and similar acids; (2) acidic protons present in the parent compound are (a) metal ions, such as alkali metal ions, alkaline earth ions, or aluminum ions Or by alkali metals such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, lithium hydroxide, zinc hydroxide, and barium hydroxide, or alkaline earth metal hydroxides, ammonia Substituted or (b) ammonia Methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N, N'-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzyl When coordinated with an organic base such as an aliphatic, alicyclic, or aromatic organic amine, such as phenethylamine, N-methylglucamine piperazine, tris (hydroxymethyl) -aminomethane, tetramethylammonium hydroxide, etc. A salt formed on any of

  Salts further include, for example, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and when the compound contains basic functionality, hydrohalides such as hydrochloride, and hydrobromide, Sulfate, phosphate, sulfamate, nitrate, acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate, cyclopentylpropionate, glycolate, glutarate, pyruvate, Lactate, malonate, succinate, sorbate, ascorbate, malate, maleate, fumarate, tartrate, citrate, benzoate, 3- (4-hydroxybenzoyl) Benzoate, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate ), Ethanesulfonate, 1,2-ethane-disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4- Toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo [2.2.2] -oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate Tert-butyl acetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, muconate, etc. Further included are salts of non-toxic organic or inorganic acids.

  The term “alkaryl” or “alkylaryl” includes aryl groups with an alkyl substituent. The term aralkyl or arylalkyl includes alkyl groups having an aryl substituent.

The term “purine” or “pyrimidine” base includes adenine, N ⁶ -alkylpurine, N ⁶ -acylpurine, wherein acyl is C (O) (alkyl, aryl, alkylaryl, or arylalkyl. ), N ⁶ - benzylpurine, N ⁶ - Haropurin, N ⁶ - vinyl purine, N ⁶ - acetylene purine, N ⁶ - Ashirupurin, N ⁶ - hydroxyalkyl purine, N ⁶ - alkylamino purine, N ⁶ - thioalkyl purine N ² -alkylpurines, N ² -alkyl-6-thiopurines, thymines, cytosines, 5-fluorocytosines, 5-methylcytosines, 6-azapyrimidines including 6-azacytosines, 2- and / or 4-mercaptopyrimidines, uracil, 5-fluorouracil containing halouracil, C ⁵ - alkyl pyrimidine, C ⁵ - benzyl pyrimidine, C ⁵ - halopyrimidines, C ⁵ - vinyl pyrimidine, C ⁵ - a Ji Ren pyrimidine, C ⁵ - acyl pyrimidines, C ⁵ - hydroxyalkyl purine, C ⁵ - amide pyrimidine, C ⁵ - cyanopyrimidine, C ⁵ - iodopyrimidine, C ⁶ - iodo - pyrimidine, C ⁵ -Br- vinyl pyrimidine, C ⁶ -Br- vinyl pyrimidine, C ⁵ - nitropyrimidine, C ⁵ - amino - pyrimidine, N ² - alkyl purine, N ² - alkyl-6-thiopurine, 5- Azashichijiniru, 5- Azaurashiriru, triazolopyrimidine pyridinylcarbonyl, imidazo Including, but not limited to, ropyridinyl, pyrrolopyrimidinyl, and pyrazolopyrimidinyl.Purine bases include guanine, adenine, hypoxanthine, 7-deazaguanine, 7-deazaadenine, 2,6-diaminopurine, and 6-chloropurine. Functional oxygen and nitrogen groups on the base can be protected or desirable as desired, including but not limited to. Such protecting groups are well known to those skilled in the art and include alkyl groups such as trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl, acetyl, and propionyl, and acyl groups, methanesulfonyl, and Contains p-toluenesulfonyl.

The term “acyl” or “O-linked ester” includes a group of formula C (O) R ′, where R ′ is a linear, branched, or cyclic alkyl (including lower alkyl). , Carboxylic acid residues of amino acids, aryl including phenyl, alkaryl, arylalkyl including benzyl, alkoxyalkyl including methoxymethyl, aryloxyalkyl such as phenoxymethyl; or substituted alkyl (including lower alkyl), chloro , Bromo, fluoro, iodo, aryl containing phenyl optionally substituted with C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy, alkyl sulfoni including methanesulfonyl, or sulfonate esters such as arylalkylsulfonyl, mono Di, or triphosphate, trityl, or monomethoxy-trityl, substituted Benzyl, alkaryl, arylalkyl including benzyl, alkoxyalkyl including methoxymethyl, aryloxyalkyl such as phenoxymethyl. The aryl group of the ester optimally comprises a phenyl group. In particular, acyl groups include: acetyl, trifluoroacetyl, methylacetyl, cyclopropylacetyl, propionyl, butyryl, hexanoyl, heptanoyl, octanoyl, neo-heptanoyl, phenylacetyl, 2-acetoxy-2- Phenylacetyl, diphenylacetyl, α-methoxy-α-trifluoromethyl-phenylacetyl, bromoacetyl, 2-nitro-benzeneacetyl, 4-chloro-benzeneacetyl, 2-chloro-2,2-diphenylacetyl, 2-chloro -2-phenylacetyl, trimethylacetyl, chlorodifluoroacetyl, perfluoroacetyl, fluoroacetyl, bromodifluoroacetyl, methoxyacetyl, 2-thiopheneacetyl, chlorosulfonylacetyl, 3-methoxyphenylacetyl, phenoxyacetyl Tert-butylacetyl, trichloroacetyl, monochloro-acetyl, dichloroacetyl, 7H-dodecafluoro-heptanoyl, perfluoro-heptanoyl, 7H-dodeca-fluoroheptanoyl, 7-chlorododecafluoroheptanoyl, 7-chloro-dodeca Fluoroheptanoyl, 7H-dodecafluoroheptanoyl, 7H-dodeca-fluoroheptanoyl, nona-fluoro-3,6-dioxa-heptanoyl, nona-fluoro-3,6-dioxaheptanoyl, perfluoroheptanoyl, methoxy Benzoyl, methyl 3-amino-5-phenylthiophene-2-carboxyl, 3,6-dichloro-2-methoxy-benzoyl, 4- (1,1,2,2-tetrafluoro-ethoxy) -benzoyl, 2-bromo -Propionyl, omega-aminocapryl, decanoyl, n-pentadecanoyl, stearyl, 3-cyclopentyl-propionyl 1-benzene-carboxyl, O-acetylmandelyl, pivaloylacetyl, 1-adamantane-carboxyl, cyclohexane-carboxyl, 2,6-pyridinedicarboxyl, cyclopropane-carboxyl, cyclobutane-carboxyl, perfluorocyclohexylcarboxyl, 4-methylbenzoyl, chloromethylisoxazolylcarbonyl, perfluorocyclohexylcarboxyl, crotonyl, 1-methyl-1H-indazole-3-carbonyl, 2-propenyl, isovaleryl, 1-pyrrolidinecarbonyl, 4-phenylbenzoyl.

  The term “amino acid” includes naturally occurring and synthetic α, β, γ, or δ amino acids and is found in proteins, ie glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, Including but not limited to proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, and histidine. In a preferred embodiment, the amino acid is of the L-configuration. Alternatively, the amino acids are alanyl, valinyl, leucinyl, isoleucinyl, prolinyl, phenylalanyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, arginyl, histidinyl, β-arazinyl, , Β-valinyl, β-leucinyl, β-isoleucinyl, β-prolinyl, β-phenylalanyl, β-tryptophanyl, β-methioninyl, β-glycinyl, β-serinyl, β-threoninyl, β-cysteinyl, β-tyrosinyl , Β-asparaginyl, β-glutaminyl, β-aspartoyl, β-glutaroyl, β-lydinyl, β-arginyl, or β-histidinyl derivatives.

  As used herein, the term “substantially free” or “substantially absent” with respect to a nucleoside composition includes at least 85%, or 90% by weight of the indicated enantiomer of the nucleoside. A nucleoside composition comprising preferably 95%, 98%, 99%, or 100% by weight. In preferred embodiments, in the methods and compounds of the invention, the compound is substantially free of enantiomers.

  Similarly, the term “isolated” with respect to a nucleoside composition includes at least 85%, 90%, 95%, 98%, 99% to 100% by weight of the nucleoside, Nucleoside compositions containing other chemical species or enantiomers are included.

  A “solvate” includes a compound provided herein, or a salt thereof, and further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

  The term “host” as used herein includes established cell lines and any single cell or multicellular organism in which viruses, including animals, preferably humans, can replicate. Alternatively, the host can carry a portion of the Flaviviridae viral genome whose replication, or function, can be altered by the compounds of the present invention. The term host specifically includes infected cells, flaviviridae genomes, and animals, particularly primates (including chimpanzees), and cells that have been transfected in whole or in part. In most animal applications of the present invention, the host is a human patient. However, veterinary applications are also clearly anticipated by the present invention (such as chimpanzees) in certain indicators.

  As used herein, the terms “subject” and “patient” are used interchangeably herein. The terms “subject” and “subject group” refer to non-primates (eg, cows, pigs, horses, cats, dogs, rats, and mice), and primates (eg, monkeys such as cynomolgus monkeys, chimpanzees, and humans). ), For example, animals such as mammals including humans. In one embodiment, the subject is resistant or refractory to current treatment for hepatitis C infection. In another embodiment, the subject is a domestic animal (eg, horse, cow, pig, etc.), or pet (eg, dog or cat). In one embodiment, the subject is a human.

  The terms “therapeutic agent” and “therapeutic agents” as used herein refer to any agent that can be used in the treatment or prevention of a disorder, or one or more symptoms thereof. In certain embodiments, the term “therapeutic agent” includes a compound provided herein. In one embodiment, the therapeutic agent is known or used for or currently used for the treatment or prevention of a disorder, or one or more symptoms thereof. Is a drug.

  “Therapeutically effective amount” includes an amount of a compound or composition that, when administered to a subject for treating a disease, sufficiently exerts the therapeutic effect for such disease. A “therapeutically effective amount” can vary depending on, inter alia, the compound, the disease, and its severity, and the age, weight, etc., of the subject to be treated.

  “Treating” or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating a disease or disorder present in a subject. In another embodiment, “treating” or “treatment” includes ameliorating at least one physical parameter, which may not be distinguishable by the subject. In yet another embodiment, “treating” or “treatment” refers to a disease or disorder, either physically (eg, stabilization of identifiable symptoms), or physiological (eg, physical parameters). Adjustment of either or both of the above. In yet another embodiment, “treating” or “treatment” includes delaying the onset of the disease or disorder.

  As used herein, the terms “prophylactic agent” and “prophylactic agents” used refer to any agent (s) that can be used to prevent a disorder, or one or more symptoms thereof. Say. In certain embodiments, the term “prophylactic agent” includes a compound provided herein. In certain other embodiments, the term “prophylactic agent” does not refer to a compound provided herein. For example, a prophylactic agent is known or used for, or currently used to prevent or prevent the onset, onset, progression, and / or severity of a disorder. Is a drug.

  As used herein, the phrase “prophylactically effective amount” includes the prevention, or reduction, of the onset, recurrence, or onset of one or more symptoms associated with a disorder (or another therapy ( For example, an amount of therapy (eg, prophylactic agent) that is sufficient (to enhance or improve the prophylactic effect of another prophylactic agent).

(Compound)
Various phosphoramidate and phosphonoamidate compounds of the therapeutic agent can be formed using methods available in the art and disclosed herein. Such compounds can be used in some embodiments to enhance delivery of drugs to the liver. In one embodiment, the compound is S-acyl-2-thioethyl phosphoramidate, or an S-acyl-2-thioethyl phosphonoamidate derivative, such as S-pivaloyl-2-thioethyl phosphoramidate, S-hydroxypivaloyl-2-thioethyl phosphoroamidate, S-pivaloyl-2-thioethylphosphonoamidate, or S-hydroxypivaloyl-2-thioethylphosphonoamidate. Therapeutic agents that can be derivatized into compound forms include reactive groups for attachment of phosphoramidate or phosphonoamidate moieties including, but not limited to, nucleosides and nucleoside analogs, including acyclic nucleosides. Or an antiviral agent derivatized to include. In addition, therapeutic agents that can be derivatized into compound forms include nucleosides, including acyclic nucleosides and nucleoside analogs, but are derivatized to form phosphoramidate or phosphonoamidate moieties. An antiviral agent that includes or is derivatized to include a phosphate or phosphonate that can be.

を含む。
ホスホラミダート又はホスホノアミダートヌクレオシド化合物の例には：

を含む。 Nucleosides that can be derivatized include any R ¹ as disclosed herein. For example, examples of nucleosides that can be derivatized to include phosphoramidates or phosphonoamidates at the 5 ′, 3 ′, or 2 ′ positions include:

including.
Examples of phosphoramidate or phosphonoamidate nucleoside compounds include:

including.

  Other nucleosides described herein and known in the art, as well as phosphoramidate or phosphonoamidate compounds of nucleoside analogs, can be formed as described herein and liver damage Can be used for treatment. The phosphoramidate or phosphonoamidate moiety can be, for example, in the 5 ′ position.

、又はその医薬として許容し得る塩、溶媒和物、立体異性形態、互変異性、若しくは多形形態であり、式中；
R^yは、全て任意に置換された、アルキル、アルケニル、アルキニル、アリール、アリールアルキル、シクロアルキル、シクロアルケニル、アミノ、ヘテロシクリル、又はヘテロアリールであり、
R^a、及びR^bは、以下の通りに選択され：
i）R^a、及びR^bは、それぞれ独立して、全て任意に置換された、水素、アルキル、カルボキシアルキル、ヒドロキシアルキル、ヒドロキシアリールアルキル、アシルオキシアルキル、アミノカルボニルアルキル、アルコキシカルボニルアルキル、アリール、アリールアルキル、シクロアルキル、ヘテロアリール、若しくはヘテロシクリルであるか；又は、
ii）R^a、及びR^bは、これらが置換される窒素原子と共に3〜7員の複素環、又はヘテロアリール環を形成し；かつ、
R¹は、抗ウイルス薬である（これには、抗ウイルス薬のヒドロキシ基からの水素の除去によって誘導体化できる部分を含む）。
特定の実施態様において、式IIa、又はIIbの化合物は、R^yがtert-ブチル、又はヒドロキシ-tert-ブチルであるときに、R¹が3'-アジド-2',3'-ジデオキシチミジンではないことを条件として選択される。 In one embodiment, provided herein are compounds that are useful for the treatment of liver disorders, including HBV and / or HCV infection, and salts thereof, and compositions comprising the compounds. In one embodiment, the phosphoramidate or phosphonoamidate compound provided herein is a compound of IIa or IIb:

Or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric or polymorphic form thereof, wherein:
R ^y is all optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, amino, heterocyclyl, or heteroaryl;
R ^a and R ^b are selected as follows:
i) R ^a and R ^b are each independently optionally substituted hydrogen, alkyl, carboxyalkyl, hydroxyalkyl, hydroxyarylalkyl, acyloxyalkyl, aminocarbonylalkyl, alkoxycarbonylalkyl, aryl, aryl Is alkyl, cycloalkyl, heteroaryl, or heterocyclyl; or
ii) R ^a and R ^b together with the nitrogen atom to which they are substituted form a 3-7 membered heterocycle or heteroaryl ring; and
R ¹ is an antiviral drug (including a moiety that can be derivatized by removal of hydrogen from the hydroxy group of the antiviral drug).
In certain embodiments, a compound of Formula IIa or IIb is selected from R ¹ is 3′-azido-2 ′, 3′-dideoxythymidine when R ^y is tert-butyl or hydroxy-tert-butyl. It is selected on the condition that there is not.

In certain embodiments, R ¹ , R ^a , R ^b , and R ^y are optionally substituted with one or more substituents as described in the definitions.

In certain embodiments, the compound is of Formula IIa or IIb, wherein R ^y is alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, amino, heterocyclyl, or heteroaryl. Yes;
R ^a and R ^b are each independently an optionally substituted hydrogen, alkyl, carboxyalkyl, hydroxyalkyl, hydroxyarylalkyl, acyloxyalkyl, aminocarbonylalkyl, alkoxycarbonylalkyl, aryl, arylalkyl, Cycloalkyl, heteroaryl, or heterocyclyl; and
R ¹ is an antiviral drug (including a moiety that can be derivatized by removal of hydrogen from the hydroxy group of the antiviral drug).

In one embodiment, R ¹ is a nucleoside comprising a cyclic or acyclic sugar, including any nucleoside described herein or known in the art, or analogs thereof, or It is an analog.

Exemplary nucleoside drugs useful for the treatment of hepatitis C infection that can be derivatized as described herein are as follows:

Exemplary non-nucleoside drugs that can be derivatized as described herein are as follows:

Exemplary nucleoside drugs useful for the treatment of hepatitis B infection that can be derivatized as described herein are as follows:

Acyclovir, L-ddA, or D-ddA phosphoramidates or phosphonoamidate compounds can be administered for the treatment of hepatitis B, examples of which are given below:

の例によって示したように、本明細書において式に示したホスホノアミダート部分に組み込むことができる。 If the nucleoside analog already contains the following phosphonate: the phosphonate group is the phosphonoamidate of adefovir:

Can be incorporated into the phosphonoamidate moiety shown in the formulas herein.

の特定の実施態様において、部分：

は、非環式ヌクレオシドホスホナート、すなわち：

である薬物に由来し、これは、例えばPMEA（9-[2-(ホスホノメトキシ）エチル］アデニン（アデフォビル）である。 Thus, the following compound of formula IIa:

In certain embodiments of:

Is an acyclic nucleoside phosphonate, ie:

This is, for example, PMEA (9- [2- (phosphonomethoxy) ethyl] adenine (adefovir).

In certain embodiments according to formula IIa or IIb, R ^y is substituted alkyl, such as hydroxyalkyl or aminoalkyl; and R ^a and R ^b are independently hydrogen, alkyl, substituted Alkyl, benzyl, or substituted benzyl such as hydroxy-substituted or amino-substituted alkyl or benzyl. In another embodiment, R ^y is -OR ^c , -C (R ^c ) ₃ , or -NHR ^c , wherein each R ^c is independently alkyl, substituted alkyl, aryl, or Substituted aryl, such as hydroxy-substituted or amino-substituted alkyl or aryl; and R ^a and R ^b are independently hydrogen, alkyl, substituted alkyl, benzyl, or substituted benzyl, such as hydroxy Substituted or amino substituted alkyl or benzyl.

In a further embodiment, R ^a and R ^b are independently benzyl, or substituted alkyl. In a further embodiment, R ^y is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, R ^y is —C (CH ₃ ) CH ₂ OH. In certain embodiments according to this paragraph, R ² and R ³ are each hydrogen, R ^a is hydrogen, R ^b is —CH ₂ —C ₆ H ₅ , and R ^y Is —C (CH ₃ ) ₂ CH ₂ OH.

In one embodiment, R ^y is alkyl or hydroxyalkyl. In one embodiment, R ^y is methyl, tert-butyl, hydroxy-tert-butyl, or hydroxyethyl. In certain embodiments, R ^y is —C (CH ₃ ) ₂ CH ₂ OH.

In one embodiment, R ^a and R ^b are each independently hydrogen, alkyl, carboxyalkyl, hydroxyalkyl, hydroxyarylalkyl, acyloxyalkyl, aminocarbonylalkyl, alkoxycarbonylalkyl, aryl, or arylalkyl. Yes, where the alkyl group can be further substituted with one or more substituents. In one embodiment, at least one of R ^a or R ^b is other than hydrogen. In one embodiment, R ^a and R ^b are each independently hydrogen, methyl, or benzyl.

In certain embodiments, R ^y is —C (CH ₃ ) ₂ CH ₂ OH, and R ^a and R ^b are each independently hydrogen, methyl, or benzyl. In certain embodiments, R ^y is —C (CH ₃ ) ₂ CH ₂ OH, R ^a is hydrogen, and R ^b is benzyl.

の化合物であり、
式中、R¹、及びR^yは、IIa、又はIIbにおいて定義したとおりである。
式IIIa、b、c、又はdの特定の実施態様において：
R^yは、置換されたアルキル、例えばヒドロキシアルキル、又はアミノアルキルであり；及び、
別の実施態様において、R^yは、-OR^c、-C(R^c)₃、又は-NHR^cであり、式中それぞれのR^cは、独立してアルキル、置換されたアルキル、アリール、又は置換されたアリール、例えばヒドロキシ置換若しくはアミノ置換されたアルキル又はアリールであり；かつR^a、及びR^bは、独立して水素、アルキル、置換されたアルキル、ベンジル、又は置換されたベンジル、例えばヒドロキシ置換、若しくはアミノ置換されたアルキル、又はヒドロキシ-、アミノ-、アルキル-、ハロアルキル-、若しくはトリフルオロメチル-置換されたベンジルである。特定の実施態様において、R^a、及びR^bは、これらが置換される窒素原子と共に3〜7員の複素環、又はヘテロアリール環を形成する。
一つの実施態様において、R^yは、アルキル、又はヒドロキシアルキルである。一つの実施態様において、R^yは、メチル、tert-ブチル、ヒドロキシ-tert-ブチル、又はヒドロキシエチルである。一つの実施態様において、R^yは、-C(CH₃)₂CH₂OHである。 In another embodiment, the compounds provided herein have the formula:

A compound of
In the formula, R ¹ and R ^y are as defined in IIa or IIb.
In certain embodiments of formula IIIa, b, c, or d:
R ^y is substituted alkyl, such as hydroxyalkyl or aminoalkyl; and
In another embodiment, R ^y is -OR ^c , -C (R ^c ) ₃ , or -NHR ^c , wherein each R ^c is independently alkyl, substituted alkyl, aryl, or Substituted aryl, such as hydroxy-substituted or amino-substituted alkyl or aryl; and R ^a and R ^b are independently hydrogen, alkyl, substituted alkyl, benzyl, or substituted benzyl, such as hydroxy Substituted or amino-substituted alkyl, or hydroxy-, amino-, alkyl-, haloalkyl-, or trifluoromethyl-substituted benzyl. In certain embodiments, R ^a and R ^b together with the nitrogen atom to which they are substituted form a 3-7 membered heterocycle, or heteroaryl ring.
In one embodiment, R ^y is alkyl or hydroxyalkyl. In one embodiment, R ^y is methyl, tert-butyl, hydroxy-tert-butyl, or hydroxyethyl. In one embodiment, R ^y is —C (CH ₃ ) ₂ CH ₂ OH.

In certain embodiments according to formula IIIa or IIIb, R ^y is substituted alkyl, such as hydroxyalkyl or aminoalkyl. In another embodiment, R ^y is -OR ^c , -C (R ^c ) ₃ , or -NHR ^c , wherein each R ^c is independently alkyl, substituted alkyl, aryl, or Substituted aryl, such as hydroxy or amino substituted alkyl or aryl. In a further embodiment, R ^y is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, R ^y is —C (CH ₃ ) ₂ CH ₂ OH.

であり、
式中、R¹、R^a、及びR^bは、例えば式IIa、又はIIbにおいて定義したとおりである。 In another embodiment, a compound provided herein has a compound of formula:

And
In the formula, R ¹ , R ^a , and R ^b are as defined in, for example, formula IIa or IIb.

In certain embodiments of formula IVa or IVb:
R ¹ is an antiviral agent such as a nucleoside or a nucleoside derivative; and
R ^a and R ^b are each independently hydrogen, alkyl, substituted alkyl, benzyl, or substituted benzyl, such as hydroxy-substituted or amino-substituted alkyl, or hydroxy-, amino-, alkyl- , Haloalkyl-, or trifluoromethyl-substituted benzyl. In a further embodiment, R ^a and R ^b are independently H, benzyl, or substituted alkyl. In certain embodiments, R ^a and R ^b together with the nitrogen atom to which they are substituted form a 3-7 membered heterocycle, or heteroaryl ring.

In certain embodiments of formula IVa or IVb:
R ¹ is an antiviral agent such as a nucleoside or a nucleoside derivative; and
R ^a and R ^b are each independently an optionally substituted hydrogen, alkyl, carboxyalkyl, hydroxyalkyl, hydroxyarylalkyl, acyloxyalkyl, aminocarbonylalkyl, alkoxycarbonylalkyl, aryl, arylalkyl, Cycloalkyl, heteroaryl, or heterocyclyl; and
Wherein in one embodiment, R ^a and R ^b are one of H and the other is alkyl optionally substituted with aryl, benzyl, or heteroaryl, each optionally substituted The

の化合物であり、
式中、R¹は、IIa、又はIIbにおいて定義したとおりである。 In another embodiment, the compounds provided herein have the formula:

A compound of
In the formula, R ¹ is as defined in IIa or IIb.

In certain embodiments, R ¹ is an HCV virus selected from ribavirin, viramidine, 2′-C-methylcytidine, 2′-C-methylguanosine, baropicitabine (NM 283), MK-0608, and PSI-6130 Antiviral nucleoside analogues useful for the treatment of infection. As used herein, an analog of R ¹ nucleoside, such as acyclovir, itself contains a phosphonate group: the phosphonate is in the form of a phosphonoamidate of the formula disclosed herein. Can be. Thus, for example, in formula Va or Vb, the R ¹ P (O) O-fragment is derived from a nucleoside analog containing a phosphonate.

In certain embodiments, R ¹ is lamivudine (Epivir-HBV, Zeffix, or Heptodin), adefovir, entecavir (Baraclude), terbivudine (Tyzeka, Sebivo) , Emtricitabine (FTC), clevudine (L-FMAU), viread (tenofovir), torcitabine, valtorcitabine (monomoval LdC), amdoxovir (DAPD), and RCV (Racivir) Are useful antiviral nucleoside analogs for the treatment of HBV viral infections selected from:

Additional exemplary antiviral nucleoside analogs that can be used as R ¹ are disclosed in International Publication Nos. WO2005021568; WO2006094347, and WO2006093987, and US Patent Publication No. US20050215510.

In certain embodiments, R ¹ is a non-nucleoside antiviral agent useful for the treatment of an HBV viral infection selected from resiquimod or celgosivir.

In one embodiment, R ¹ is an immunosuppressive drug such as combretastatin A-4, mycophenolic acid, pentostatin, nelarabine, or mitoxantrone.

In one embodiment, R ¹ is an interference, RNA (iRNA) based antiviral agent including a small interfering RNA (siRNA) based antiviral agent. Such compounds are described in International Application Publication Nos. WO / 03/070750 and WO2005 / 012525, U.S. Patent Nos. 7,176,304; 7,109,165; 7,041,817; 7,034,009; 7,022,828; 6,852,535 and 6,849,726. , As well as in US Patent Publication No. US2004 / 0209831.

の化合物であり、
式中、R^a、R^b、及びR^yは、式IIa、又はIIbにおいて定義したとおりであり、かつR²、及びR³は、それぞれ独立してH；直鎖、分枝、又は環状のアルキル；アシル（低級アシルを含む）；CO-アルキル、CO-アリール、CO-アルコキシアルキル、CO-アリールオキシアルキル、CO-置換されたアリール、メタンスルホニルを含むアルキル又はアリールアルキルスルホニルなどのスルホナートエステル、及びベンジルであって、式中フェニル基は、任意に置換されており；アルキルスルホニル、アリールスルホニル、アラルキルスルホニル、リン脂質などの脂質；アミノ酸；及びアミノ酸残基、炭水化物；ペプチド；コレステロール；例えばインビボで投与されたときに、R²、及び／又はR³が独立してH、又はホスフェート（モノ、ジ、又はトリホスフェートを含む）である化合物を提供することができるその他の医薬として許容し得る脱離基か；又はR²、及びR³は、アルキル、エステル、又はカルバメート結合によって環状基を形成するように連結される。それぞれのR^Lは、独立してH、カルバミル、直鎖、分枝、又は環状のアルキルであり；アシル（低級アシルを含む）；CO-アルキル、CO-アリール、CO-アルコキシアルキル、CO-アリールオキシアルキル、CO-置換されたアリール、メタンスルホニルを含むアルキル又はアリールアルキルスルホニルなどのスルホナートエステル、及びベンジルであって、式中フェニル基は、任意に置換されており；アルキルスルホニル、アリールスルホニル、アリールアルキルスルホニル、リン脂質などの脂質；アミノ酸；アミノ酸残基；又は炭水化物である。特定の実施態様において、R²、及びR³は、それぞれ水素であり、R^aは、水素であり、R^bは、-CH₂-C₆H₅であり、かつR^yは、-C(CH₃)₂CH₂OHである。このパラグラフに従った特定の実施態様において、R²、及びR³は、それぞれHであり；R^yは、置換されたアルキル、例えばヒドロキシアルキル、又はアミノアルキルであり；かつR^a、及びR^bは、独立して水素、アルキル、置換されたアルキル、ベンジル、又は置換されたベンジル、例えばヒドロキシ置換若しくはアミノ置換されたアルキル又はベンジルである。別の実施態様において、R²、及びR³は、それぞれHであり；R^yは、-OR^c、-C(R^c)₃、又は-NHR^cであり、式中それぞれのR^cは、独立してアルキル、置換されたアルキル、アリール、又は置換されたアリール、例えばヒドロキシ置換、若しくはアミノ-置換されたアルキル、又はアリールであり；かつR^a、及びR^bは、独立して水素、アルキル、置換されたアルキル、ベンジル、又は置換されたベンジル、例えばヒドロキシ置換若しくはアミノ置換されたアルキル又はベンジルである。さらなる実施態様において、R²、及びR³は、それぞれHであり；R^a、及びR^bは、独立してベンジル、又は置換されたアルキルである。さらなる実施態様において、R²、及びR³は、それぞれHであり；R^yは、アルキル、及びヒドロキシアルキルからなる群から選択される。特定の実施態様において、R²、及びR³は、それぞれHであり；R^yは、-C(CH₃)₂CH₂OHである。 In another embodiment, the compounds provided herein have the formula:

A compound of
Wherein R ^a , R ^b , and R ^y are as defined in formula IIa or IIb, and R ² and R ³ are each independently H; linear, branched, or cyclic Alkyl; acyl (including lower acyl); sulfonate esters such as CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkyl including methanesulfonyl or arylalkylsulfonyl , And benzyl, wherein the phenyl group is optionally substituted; lipids such as alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, phospholipids; amino acids; and amino acid residues, carbohydrates; peptides; cholesterol; in that when administered, R ^2, and / or R ³ is independently H, or phosphates (mono-, di-, or triphosphate Leaving group or other pharmaceutically acceptable which is capable of providing a compound which is included); or R ^2, and R ³ of which are connected to form a cyclic alkyl, ester, or by carbamate linkages . Each R ^L is independently H, carbamyl, linear, branched, or cyclic alkyl; acyl (including lower acyl); CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryl Sulfonate esters such as oxyalkyl, CO-substituted aryl, alkyl including methanesulfonyl or arylalkylsulfonyl, and benzyl, wherein the phenyl group is optionally substituted; alkylsulfonyl, arylsulfonyl, A lipid such as arylalkylsulfonyl, phospholipid; amino acid; amino acid residue; or carbohydrate. In certain embodiments, R ² and R ³ are each hydrogen, R ^a is hydrogen, R ^b is —CH ₂ —C ₆ H ₅ , and R ^y is —C ( CH ₃ ) ₂ CH ₂ OH. In particular embodiments according to this paragraph, R ² and R ³ are each H; R ^y is substituted alkyl, such as hydroxyalkyl or aminoalkyl; and R ^a and R ^b Are independently hydrogen, alkyl, substituted alkyl, benzyl, or substituted benzyl, such as hydroxy- or amino-substituted alkyl or benzyl. In another embodiment, R ² and R ³ are each H; R ^y is —OR ^c , —C (R ^c ) ₃ , or —NHR ^c , wherein each R ^c is Independently alkyl, substituted alkyl, aryl, or substituted aryl, eg, hydroxy-substituted or amino-substituted alkyl, or aryl; and R ^a and R ^b are independently hydrogen, alkyl , Substituted alkyl, benzyl, or substituted benzyl, such as hydroxy- or amino-substituted alkyl or benzyl. In a further embodiment, R ² and R ³ are each H; R ^a and R ^b are independently benzyl, or substituted alkyl. In a further embodiment, R ² and R ³ are each H; R ^y is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, R ² and R ³ are each H; R ^y is —C (CH ₃ ) ₂ CH ₂ OH.

の化合物であり、式中、R^a、R^b、及びR^yは、式IIa、又はIIbにおいて定義したとおりであり、かつR^eは、水素、又はアルキルである。それぞれのR^Lは、独立してH、カルバミル、直鎖、分枝、又は環状のアルキルであり；アシル（低級アシルを含む）；CO-アルキル、CO-アリール、CO-アルコキシアルキル、CO-アリールオキシアルキル、CO-置換されたアリール、メタンスルホニルを含むアルキル又はアリールアルキルスルホニルなどのスルホナートエステル、及びベンジルであって、式中、フェニル基は、任意に置換されており；アルキルスルホニル、アリールスルホニル、アラルキルスルホニル、リン脂質などの脂質；アミノ酸；アミノ酸残基；又は炭水化物である。特定の実施態様において、R^eは、メチル、エチル、又はプロピルであり、かつR^aは、水素であり、R^bは、-CH₂-C₆H₅であり、かつR^yは、-C(CH₃)₂CH₂OHである。このパラグラフに従った特定の実施態様において、R²、及びR³は、それぞれHであり；R^yは、置換されたアルキル、例えばヒドロキシアルキル、又はアミノアルキルであり；かつR^a、及びR^bは、独立して水素、アルキル、置換されたアルキル、ベンジル、又は置換されたベンジル、例えばヒドロキシ置換若しくはアミノ置換されたアルキル又はベンジルである。別の実施態様において、R^eは、メチル、エチル、又はプロピルであり；R²、及びR³は、それぞれHであり；R^yは、-OR^c、-C(R^c)₃、又は-NHR^cであり、式中それぞれのR^cは、独立してアルキル、置換されたアルキル、アリール、又は置換されたアリール、例えばヒドロキシ置換若しくはアミノ置換されたアルキル又はアリールであり；かつR^a、及びR^bは、独立して水素、アルキル、置換されたアルキル、ベンジル、又は置換されたベンジル、例えばヒドロキシ置換若しくはアミノ置換されたアルキル又はベンジルである。さらなる実施態様において、R^eは、メチル、エチル、又はプロピルであり；R²、及びR³は、それぞれHであり；R^a、及びR^bは、独立してベンジル、又は置換されたアルキルである。さらなる実施態様において、R²、及びR³は、それぞれHであり；R^yは、アルキル、及びヒドロキシアルキルからなる群から選択される。特定の実施態様において、R^eは、メチル、エチル、又はプロピルであり；R²、及びR³は、それぞれHであり；R^yは、-C(CH₃)₂CH₂OHである。このパラグラフに従った特定の実施態様において、R¹は、その内容が参照としてその全体が本明細書に組み込まれる米国特許出願公開番号US2006/0111324 A1に記載されたヌクレオシドから選択される。 In another embodiment, the compounds provided herein have the formula:

Wherein R ^a , R ^b , and R ^y are as defined in formula IIa or IIb, and ^Re is hydrogen or alkyl. Each R ^L is independently H, carbamyl, linear, branched, or cyclic alkyl; acyl (including lower acyl); CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryl Oxyalkyl, CO-substituted aryl, sulfonate esters such as alkyl or arylalkylsulfonyl, including methanesulfonyl, and benzyl, wherein the phenyl group is optionally substituted; alkylsulfonyl, arylsulfonyl A lipid such as aralkylsulfonyl, phospholipid; amino acid; amino acid residue; or carbohydrate. In certain embodiments, R ^e is methyl, ethyl, or propyl, and R ^a is hydrogen, R ^b is —CH ₂ —C ₆ H ₅ , and R ^y is —C (CH ₃ ) ₂ CH ₂ OH. In particular embodiments according to this paragraph, R ² and R ³ are each H; R ^y is substituted alkyl, such as hydroxyalkyl or aminoalkyl; and R ^a and R ^b Are independently hydrogen, alkyl, substituted alkyl, benzyl, or substituted benzyl, such as hydroxy- or amino-substituted alkyl or benzyl. In another embodiment, R ^e is methyl, ethyl, or propyl; R ² and R ³ are each H; R ^y is —OR ^c , —C (R ^c ) ₃ , or — NHR ^c , wherein each R ^c is independently alkyl, substituted alkyl, aryl, or substituted aryl, such as hydroxy-substituted or amino-substituted alkyl or aryl; and R ^a , and R ^b is independently hydrogen, alkyl, substituted alkyl, benzyl, or substituted benzyl, such as hydroxy- or amino-substituted alkyl or benzyl. In a further embodiment, R ^e is methyl, ethyl, or propyl; R ² and R ³ are each H; R ^a and R ^b are independently benzyl, or substituted alkyl. is there. In a further embodiment, R ² and R ³ are each H; R ^y is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, R ^e is methyl, ethyl, or propyl; R ² and R ³ are each H; R ^y is —C (CH ₃ ) ₂ CH ₂ OH. In a particular embodiment according to this paragraph, R ¹ is selected from the nucleosides described in US Patent Application Publication No. US2006 / 0111324 A1, the contents of which are hereby incorporated by reference in their entirety.

の化合物であり、式中、R^a、R^b、及びR^yは、式IIa、又はIIbにおいて定義したとおりである。それぞれのR^Lは、独立してH、カルバミル、直鎖、分枝、又は環状のアルキル；アシル（低級アシルを含む）；CO-アルキル、CO-アリール、CO-アルコキシアルキル、CO-アリールオキシアルキル、CO-置換されたアリール、メタンスルホニルを含むアルキル又はアリールアルキルスルホニルなどのスルホナートエステル、及びベンジルであって、式中フェニル基は、任意に置換されており；アルキルスルホニル、アリールスルホニル、アリールアルキルスルホニル、リン脂質などの脂質；アミノ酸；アミノ酸残基；又は炭水化物である。このパラグラフに従った特定の実施態様において、それぞれのR^Lは、水素であり、R^yは、置換されたアルキル、例えばヒドロキシアルキル、又はアミノアルキルであり；かつR^a、及びR^bは、独立して水素、アルキル、置換されたアルキル、ベンジル、又は置換されたベンジル、例えばヒドロキシ置換若しくはアミノ置換されたアルキル又はベンジルである。別の実施態様において、それぞれのR^Lは、水素であり、R^yは、-OR^c、-C(R^c)₃、又は-NHR^cであり、式中それぞれのR^cは、独立してアルキル、置換されたアルキル、アリール、又は置換されたアリール、例えばヒドロキシ置換若しくはアミノ置換されたアルキル又はアリールであり；かつR^a、及びR^bは、独立して水素、アルキル、置換されたアルキル、ベンジル、又は置換されたベンジル、例えばヒドロキシ置換若しくはアミノ置換されたアルキル又はベンジルである。さらなる実施態様において、それぞれのR^Lは、水素であり、R^a、及びR^bは、独立してベンジル、又は置換されたアルキルである。さらなる実施態様において、R^yは、アルキル、及びヒドロキシアルキルからなる群から選択される。特定の実施態様において、それぞれのR^Lは、水素であり、かつR^yは、-C(CH₃)₂CH₂OHである。 In another embodiment, the compounds provided herein have the formula:

Wherein R ^a , R ^b , and R ^y are as defined in formula IIa or IIb. Each R ^L is independently H, carbamyl, linear, branched, or cyclic alkyl; acyl (including lower acyl); CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl , Sulfonate esters such as CO-substituted aryl, alkyl containing methanesulfonyl or arylalkylsulfonyl, and benzyl, wherein the phenyl group is optionally substituted; alkylsulfonyl, arylsulfonyl, arylalkyl Lipids such as sulfonyl and phospholipid; amino acids; amino acid residues; or carbohydrates. In certain embodiments according to this paragraph, each R ^L is hydrogen, R ^y is substituted alkyl, such as hydroxyalkyl, or aminoalkyl; and R ^a and R ^b are independently Hydrogen, alkyl, substituted alkyl, benzyl, or substituted benzyl, such as hydroxy- or amino-substituted alkyl or benzyl. In another embodiment, each R ^L is hydrogen and R ^y is —OR ^c , —C (R ^c ) ₃ , or —NHR ^c , wherein each R ^c is independently Alkyl, substituted alkyl, aryl, or substituted aryl, such as hydroxy- or amino-substituted alkyl or aryl; and R ^a and R ^b are independently hydrogen, alkyl, substituted alkyl, Benzyl, or substituted benzyl, such as hydroxy-substituted or amino-substituted alkyl or benzyl. In a further embodiment, each R ^L is hydrogen and R ^a and R ^b are independently benzyl, or substituted alkyl. In a further embodiment, R ^y is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, each R ^L is hydrogen and R ^y is —C (CH ₃ ) ₂ CH ₂ OH.

の化合物であり、 In another embodiment, the compounds provided herein have the formula:

A compound of

の化合物であり、式中、R^a、R^b、及びR^yは、式IIa、又はIIbにおいて定義したとおりである。それぞれのR^Lは、独立してH、カルバミル、直鎖、分枝、又は環状のアルキル；アシル（低級アシルを含む）；CO-アルキル、CO-アリール、CO-アルコキシアルキル、CO-アリールオキシアルキル、CO-置換されたアリール、はメタンスルホニルを含むアルキル又はアリールアルキルスルホニルなどのスルホナートエステル、及びベンジルであって、式中フェニル基は、任意に置換されており；アルキルスルホニル、アリールスルホニル、アリールアルキルスルホニル、リン脂質などの脂質；アミノ酸；アミノ酸残基；又は炭水化物である。このパラグラフに従った特定の実施態様において、それぞれのR^Lは、水素であり、R^yは、置換されたアルキル、例えばヒドロキシアルキル、又はアミノアルキルであり；かつR^a、及びR^bは、独立して水素、アルキル、置換されたアルキル、ベンジル、又は置換されたベンジル、例えばヒドロキシ置換若しくはアミノ置換されたアルキル又はベンジルである。別の実施態様において、それぞれのR^Lは、水素であり、R^yは、-OR^c、-C(R^c)₃、又は-NHR^cであり、式中それぞれのR^cは、独立してアルキル、置換されたアルキル、アリール、又は置換されたアリール、例えばヒドロキシ置換若しくはアミノ置換されたアルキル又はアリールであり；かつR^a、及びR^bは、独立して水素、アルキル、置換されたアルキル、ベンジル、又は置換されたベンジル、例えばヒドロキシ置換若しくはアミノ置換されたアルキル又はベンジルである。さらなる実施態様において、それぞれのR^Lは、水素であり、R^a、及びR^bは、独立してベンジル、又は置換されたアルキルである。さらなる実施態様において、R^yは、アルキル、及びヒドロキシアルキルからなる群から選択される。特定の実施態様において、それぞれのR^Lは、水素であり、かつR^yは、-C(CH₃)₂CH₂OHである。 In the formula, R ^a , R ^b , and R ^y are as defined in formula IIa or IIb. Each R ^L is independently H, carbamyl, linear, branched, or cyclic alkyl; acyl (including lower acyl); CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl , Sulfonate esters such as CO-substituted aryl, alkyl containing methanesulfonyl or arylalkylsulfonyl, and benzyl, wherein the phenyl group is optionally substituted; alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, Lipids such as phospholipids; amino acids; amino acid residues; or carbohydrates. In certain embodiments according to this paragraph, each R ^L is hydrogen, R ^y is substituted alkyl, such as hydroxyalkyl, or aminoalkyl; and R ^a and R ^b are independently Hydrogen, alkyl, substituted alkyl, benzyl, or substituted benzyl, such as hydroxy- or amino-substituted alkyl or benzyl. In another embodiment, each R ^L is hydrogen and R ^y is —OR ^c , —C (R ^c ) ₃ , or —NHR ^c , wherein each R ^c is independently Alkyl, substituted alkyl, aryl, or substituted aryl, such as hydroxy- or amino-substituted alkyl or aryl; and R ^a and R ^b are independently hydrogen, alkyl, substituted alkyl, Benzyl, or substituted benzyl, such as hydroxy-substituted or amino-substituted alkyl or benzyl. In a further embodiment, each R ^L is hydrogen and R ^a and R ^b are independently benzyl, or substituted alkyl. In a further embodiment, R ^y is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, each R ^L is hydrogen and R ^y is —C (CH ₃ ) ₂ CH ₂ OH. In another embodiment, the compounds provided herein have the formula:

Wherein R ^a , R ^b , and R ^y are as defined in formula IIa or IIb. Each R ^L is independently H, carbamyl, linear, branched, or cyclic alkyl; acyl (including lower acyl); CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl , CO-substituted aryl, sulfonate esters such as alkyl or arylalkylsulfonyl, including methanesulfonyl, and benzyl, wherein the phenyl group is optionally substituted; alkylsulfonyl, arylsulfonyl, aryl Lipids such as alkylsulfonyl and phospholipid; amino acids; amino acid residues; or carbohydrates. In certain embodiments according to this paragraph, each R ^L is hydrogen, R ^y is substituted alkyl, such as hydroxyalkyl, or aminoalkyl; and R ^a and R ^b are independently Hydrogen, alkyl, substituted alkyl, benzyl, or substituted benzyl, such as hydroxy- or amino-substituted alkyl or benzyl. In another embodiment, each R ^L is hydrogen and R ^y is —OR ^c , —C (R ^c ) ₃ , or —NHR ^c , wherein each R ^c is independently Alkyl, substituted alkyl, aryl, or substituted aryl, such as hydroxy- or amino-substituted alkyl or aryl; and R ^a and R ^b are independently hydrogen, alkyl, substituted alkyl, Benzyl, or substituted benzyl, such as hydroxy-substituted or amino-substituted alkyl or benzyl. In a further embodiment, each R ^L is hydrogen and R ^a and R ^b are independently benzyl, or substituted alkyl. In a further embodiment, R ^y is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, each R ^L is hydrogen and R ^y is —C (CH ₃ ) ₂ CH ₂ OH.

の化合物であり、 In another embodiment, the compounds provided herein have the formula:

A compound of

In the formula, R ^a , R ^b , and R ^y are as defined in formula IIa or IIb. Each R ^L is independently H, carbamyl, linear, branched, or cyclic alkyl; acyl (including lower acyl); CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl , Sulfonate esters such as CO-substituted aryl, alkyl containing methanesulfonyl or arylalkylsulfonyl, and benzyl, wherein the phenyl group is optionally substituted; alkylsulfonyl, arylsulfonyl, arylalkyl Lipids such as sulfonyl and phospholipid; amino acids; amino acid residues; or carbohydrates. In certain embodiments according to this paragraph, each R ^L is hydrogen, R ^y is substituted alkyl, such as hydroxyalkyl, or aminoalkyl; and R ^a and R ^b are independently Hydrogen, alkyl, substituted alkyl, benzyl, or substituted benzyl, such as hydroxy- or amino-substituted alkyl or benzyl. In another embodiment, each R ^L is hydrogen and R ^y is —OR ^c , —C (R ^c ) ₃ , or —NHR ^c , wherein each R ^c is independently Alkyl, substituted alkyl, aryl, or substituted aryl, such as hydroxy- or amino-substituted alkyl or aryl; and R ^a and R ^b are independently hydrogen, alkyl, substituted alkyl, Benzyl, or substituted benzyl, such as hydroxy-substituted or amino-substituted alkyl or benzyl. In a further embodiment, each R ^L is hydrogen and R ^a and R ^b are independently benzyl, or substituted alkyl. In a further embodiment, R ^y is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, each R ^L is hydrogen and R ^y is —C (CH ₃ ) ₂ CH ₂ OH.

の化合物であり、 In another embodiment, the compounds provided herein have the formula:

A compound of

In the formula, R ^a , R ^b , and R ^y are as defined in formula IIa or IIb. Each R ^L is independently H, carbamyl, linear, branched, or cyclic alkyl; acyl (including lower acyl); CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl , Sulfonate esters such as CO-substituted aryl, alkyl containing methanesulfonyl or arylalkylsulfonyl, and benzyl, wherein the phenyl group is optionally substituted; alkylsulfonyl, arylsulfonyl, arylalkyl Lipids such as sulfonyl and phospholipid; amino acids; amino acid residues; or carbohydrates. In certain embodiments according to this paragraph, each R ^L is hydrogen, R ^y is substituted alkyl, such as hydroxyalkyl, or aminoalkyl; and R ^a and R ^b are independently Hydrogen, alkyl, substituted alkyl, benzyl, or substituted benzyl, such as hydroxy- or amino-substituted alkyl or benzyl. In another embodiment, each R ^L is hydrogen and R ^y is —OR ^c , —C (R ^c ) ₃ , or —NHR ^c , wherein each R ^c is independently Alkyl, substituted alkyl, aryl, or substituted aryl, such as hydroxy- or amino-substituted alkyl or aryl; and R ^a and R ^b are independently hydrogen, alkyl, substituted alkyl, Benzyl, or substituted benzyl, such as hydroxy-substituted or amino-substituted alkyl or benzyl. In a further embodiment, each R ^L is hydrogen and R ^a and R ^b are independently benzyl, or substituted alkyl. In a further embodiment, R ^y is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, each R ^L is hydrogen and R ^y is —C (CH ₃ ) ₂ CH ₂ OH.

の化合物であり、
式中、R^a、R^b、及びR^yは、式IIa、又はIIbにおいて定義したとおりである。それぞれのR^Lは、独立してH、カルバミル、直鎖、分枝、又は環状のアルキル；アシル（低級アシルを含む）；CO-アルキル、CO-アリール、CO-アルコキシアルキル、CO-アリールオキシアルキル、CO-置換されたアリール、メタンスルホニルを含むアルキル又はアリールアルキルスルホニルなどのスルホナートエステル、及びベンジルであって、式中フェニル基は、任意に置換されており；アルキルスルホニル、アリールスルホニル、アリールアルキルスルホニル、リン脂質などの脂質；アミノ酸；アミノ酸残基；又は炭水化物である。このパラグラフに従った特定の実施態様において、それぞれのR^Lは、水素であり、R^yは、置換されたアルキル、例えばヒドロキシアルキル、又はアミノアルキルであり；かつR^a、及びR^bは、独立して水素、アルキル、置換されたアルキル、ベンジル、又は置換されたベンジル、例えばヒドロキシ置換若しくはアミノ置換されたアルキル又はベンジルである。別の実施態様において、それぞれのR^Lは、水素であり、R^yは-OR^c、-C(R^c)₃、又は-NHR^cであり、式中それぞれのR^cは、独立してアルキル、置換されたアルキル、アリール、又は置換されたアリール、例えばヒドロキシ置換若しくはアミノ置換されたアルキル又はアリールであり；かつR^a、及びR^bは、独立して水素、アルキル、置換されたアルキル、ベンジル、又は置換されたベンジル、例えばヒドロキシ置換若しくはアミノ置換されたアルキル又はベンジルである。さらなる実施態様において、それぞれのR^Lは、水素であり、R^a、及びR^bは独立してベンジル、又は置換されたアルキルである。さらなる実施態様において、R^yは、アルキル、及びヒドロキシアルキルからなる群から選択される。特定の実施態様において、それぞれのR^Lは、水素であり、かつR^yは-C(CH₃)₂CH₂OHである。 In another embodiment, the compounds provided herein have the formula:

A compound of
In the formula, R ^a , R ^b , and R ^y are as defined in formula IIa or IIb. Each R ^L is independently H, carbamyl, linear, branched, or cyclic alkyl; acyl (including lower acyl); CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl , Sulfonate esters such as CO-substituted aryl, alkyl containing methanesulfonyl or arylalkylsulfonyl, and benzyl, wherein the phenyl group is optionally substituted; alkylsulfonyl, arylsulfonyl, arylalkyl Lipids such as sulfonyl and phospholipid; amino acids; amino acid residues; or carbohydrates. In certain embodiments according to this paragraph, each R ^L is hydrogen, R ^y is substituted alkyl, such as hydroxyalkyl, or aminoalkyl; and R ^a and R ^b are independently Hydrogen, alkyl, substituted alkyl, benzyl, or substituted benzyl, such as hydroxy- or amino-substituted alkyl or benzyl. In another embodiment, each R ^L is hydrogen and R ^y is —OR ^c , —C (R ^c ) ₃ , or —NHR ^c , wherein each R ^c is independently alkyl , Substituted alkyl, aryl, or substituted aryl, eg, hydroxy-substituted or amino-substituted alkyl or aryl; and R ^a and R ^b are independently hydrogen, alkyl, substituted alkyl, benzyl Or substituted benzyl, for example hydroxy-substituted or amino-substituted alkyl or benzyl. In a further embodiment, each R ^L is hydrogen and R ^a and R ^b are independently benzyl, or substituted alkyl. In a further embodiment, R ^y is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, each R ^L is hydrogen and R ^y is —C (CH ₃ ) ₂ CH ₂ OH.

  In another embodiment, the compounds provided herein have the formula:

の化合物であり、

A compound of

In the formula, R ^a , R ^b , and R ^y are as defined in formula IIa or IIb. Each R ^L is independently H, carbamyl, linear, branched, or cyclic alkyl; acyl (including lower acyl); CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl , Sulfonate esters such as CO-substituted aryl, alkyl containing methanesulfonyl or arylalkylsulfonyl, and benzyl, wherein the phenyl group is optionally substituted; alkylsulfonyl, arylsulfonyl, arylalkyl Lipids such as sulfonyl and phospholipid; amino acids; amino acid residues; or carbohydrates. In certain embodiments according to this paragraph, each R ^L is hydrogen, R ^y is substituted alkyl, such as hydroxyalkyl, or aminoalkyl; and R ^a and R ^b are independently Hydrogen, alkyl, substituted alkyl, benzyl, or substituted benzyl, such as hydroxy- or amino-substituted alkyl or benzyl. In another embodiment, each R ^L is hydrogen and R ^y is —OR ^c , —C (R ^c ) ₃ , or —NHR ^c , wherein each R ^c is independently Alkyl, substituted alkyl, aryl, or substituted aryl, such as hydroxy- or amino-substituted alkyl or aryl; and R ^a and R ^b are independently hydrogen, alkyl, substituted alkyl, Benzyl, or substituted benzyl, such as hydroxy-substituted or amino-substituted alkyl or benzyl. In a further embodiment, each R ^L is hydrogen and R ^a and R ^b are independently benzyl, or substituted alkyl. In a further embodiment, R ^y is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, each R ^L is hydrogen and R ^y is —C (CH ₃ ) ₂ CH ₂ OH.

式中：
T = O、S、CH₂ CH（hal）、又はCH（hal）₂、S(O)n；
n= 1、2；
hal =ハロゲン；
R=H 、アシル（低級直鎖、及び非直鎖アルキル-C₁-C₆-をもつ、アミノ酸）、モノホスフェート、ジホスフェート、トリホスフェート、(アルキル-O)₂PO、(tBuSate-O)₂PO、環状モノホスフェートプロドラッグ、ホスホラミダートプロドラッグ（芳香族アミン、アミノ酸）などのモノホスフェートプロドラッグ；
X、及びYは、独立してH、OH、O-アルキル（低級）、O-アシル、F、NH₂、NH-アルキル、N-ジアルキル、NH-アシル、N-ジアシル、又はアジドであり；
Zは、H、アルキル、アルケニル、アルキニル、ヒドロキシメチル、フルオロメチル、又はアジドであり；
Wは、H、アルキル、アルケニル、アルキニル、ヒドロキシメチル、フルオロメチル、アジド、カルボン酸、CO₂-アルキル、シアノ、又はカルボキサミドであり；
Aは、H、アルキル、アルケニル、アルキニル、ヒドロキシメチル、フルオロメチル、アジド、カルボン酸、CO₂-アルキル、シアノ、又はカルボキサミドであり；かつ
Baseは、天然、又は修飾された塩基である。任意に、化合物は、2'位置に塩素原子を含む。 In certain embodiments, to enhance delivery of active monophosphate to the liver of an individual afflicted with HCV, 2-deoxy-2-fluoro-2-, such as the compounds described herein as examples C-ethynyl-β-D-nucleosides can be formed and lead to phosphoramidate compounds. In certain embodiments, compounds of the following formula are provided:

In the formula:
T = O, S, CH ₂ CH (hal), or CH (hal) ₂ , S (O) n;
n = 1, 2;
hal = halogen;
R = H, acyl (amino acids with lower linear and non-linear alkyl-C ₁ -C _6- ), monophosphate, diphosphate, triphosphate, (alkyl-O) ₂ PO, (tBuSate-O) ₂ monophosphate prodrugs such as PO, cyclic monophosphate prodrugs, phosphoramidate prodrugs (aromatic amines, amino acids);
X and Y are independently H, OH, O-alkyl (lower), O-acyl, F, NH ₂ , NH-alkyl, N-dialkyl, NH-acyl, N-diacyl, or azide;
Z is H, alkyl, alkenyl, alkynyl, hydroxymethyl, fluoromethyl, or azide;
W is H, alkyl, alkenyl, alkynyl, hydroxymethyl, fluoromethyl, azide, carboxylic acid, CO ₂ -alkyl, cyano, or carboxamide;
A is, H, alkyl, alkenyl, alkynyl, hydroxymethyl, fluoromethyl, azido, carboxylic acid, CO ₂ - alkyl, cyano, or a carboxamide; and
Base is a natural or modified base. Optionally, the compound contains a chlorine atom at the 2 ′ position.

の化合物であり、
式中、R^a、R^b、及びR^yは、式IIa、又はIIbにおいて定義したようにあり；Aは、H、アルキル、アルケニル、アルキニル、ヒドロキシメチル、フルオロメチル、アジド、カルボン酸、CO₂-アルキル、シアノ、又はカルボキサミドであり；かつR^b1は、ハロ、アルコキシ、又はハロアルキルである。それぞれのR^Lは、独立してH、カルバミル、直鎖、分枝、又は環状のアルキル；アシル（低級アシルを含む）；CO-アルキル、CO-アリール、CO-アルコキシアルキル、CO-アリールオキシアルキル、CO-置換されたアリール、メタンスルホニルを含むアルキル又はアリールアルキルスルホニルなどのスルホナートエステル、及びベンジルであって、式中フェニル基は、任意に置換されており；アルキルスルホニル、アリールスルホニル、アリールアルキルスルホニル、リン脂質などの脂質；アミノ酸；アミノ酸残基；又は炭水化物である。このパラグラフに従った特定の実施態様において、それぞれのR^Lは、水素であり、R^yは、置換されたアルキル、例えばヒドロキシアルキル、又はアミノアルキルであり；かつR^a、及びR^bは、独立して水素、アルキル、置換されたアルキル、ベンジル、又は置換されたベンジル、例えばヒドロキシ置換若しくはアミノ置換されたアルキル又はベンジルである。別の実施態様において、それぞれのR^Lは、水素であり、R^yは、-OR^c、-C(R^c)₃、又は-NHR^cであり、式中それぞれのR^cは、独立してアルキル、置換されたアルキル、アリール、又は置換されたアリール、例えばヒドロキシ置換若しくはアミノ置換されたアルキル又はアリールであり；かつR^a、及びR^bは、独立して水素、アルキル、置換されたアルキル、ベンジル、又は置換されたベンジル、例えばヒドロキシ置換若しくはアミノ置換されたアルキル又はベンジルである。さらなる実施態様において、それぞれのR^Lは、水素であり、R^a、及びR^bは、独立してベンジル、又は置換されたアルキルである。さらなる実施態様において、R^yは、アルキル、及びヒドロキシアルキルからなる群から選択される。特定の実施態様において、それぞれのR^Lは、水素であり、かつR^yは、-C(CH₃)₂CH₂OHである。 In another embodiment, the compounds provided herein have the formula:

A compound of
In which R ^a , R ^b , and R ^y are as defined in formula IIa or IIb; A is H, alkyl, alkenyl, alkynyl, hydroxymethyl, fluoromethyl, azide, carboxylic acid, CO ₂ -Alkyl, cyano, or carboxamide; and R ^b1 is halo, alkoxy, or haloalkyl. Each R ^L is independently H, carbamyl, linear, branched, or cyclic alkyl; acyl (including lower acyl); CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl , Sulfonate esters such as CO-substituted aryl, alkyl containing methanesulfonyl or arylalkylsulfonyl, and benzyl, wherein the phenyl group is optionally substituted; alkylsulfonyl, arylsulfonyl, arylalkyl Lipids such as sulfonyl and phospholipid; amino acids; amino acid residues; or carbohydrates. In certain embodiments according to this paragraph, each R ^L is hydrogen, R ^y is substituted alkyl, such as hydroxyalkyl, or aminoalkyl; and R ^a and R ^b are independently Hydrogen, alkyl, substituted alkyl, benzyl, or substituted benzyl, such as hydroxy- or amino-substituted alkyl or benzyl. In another embodiment, each R ^L is hydrogen and R ^y is —OR ^c , —C (R ^c ) ₃ , or —NHR ^c , wherein each R ^c is independently Alkyl, substituted alkyl, aryl, or substituted aryl, such as hydroxy- or amino-substituted alkyl or aryl; and R ^a and R ^b are independently hydrogen, alkyl, substituted alkyl, Benzyl, or substituted benzyl, such as hydroxy-substituted or amino-substituted alkyl or benzyl. In a further embodiment, each R ^L is hydrogen and R ^a and R ^b are independently benzyl, or substituted alkyl. In a further embodiment, R ^y is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, each R ^L is hydrogen and R ^y is —C (CH ₃ ) ₂ CH ₂ OH.

の化合物であり、
式中、R^a、R^b、及びR^yは、式IIa、又はIIbにおいて定義したとおりである。特定の実施態様において、R^aは、水素であり、R^bは、-CH₂-C₆H₅であり、かつR^yは、-C(CH₃)₂CH₂OHである。このパラグラフに従った特定の実施態様において、R^yは、置換されたアルキル、例えばヒドロキシアルキル、又はアミノアルキルであり；かつR^a、及びR^bは、独立して水素、アルキル、置換されたアルキル、ベンジル、又は置換されたベンジル、例えばヒドロキシ置換若しくはアミノ置換されたアルキル又はベンジルである。別の実施態様において、R^yは、-OR^c、-C(R^c)₃、又は-NHR^cであり、式中それぞれのR^cは、独立してアルキル、置換されたアルキル、アリール、又は置換されたアリール、例えばヒドロキシ置換若しくはアミノ置換されたアルキル又はアリールであり；かつR^a、及びR^bは、独立して水素、アルキル、置換されたアルキル、ベンジル、又は置換されたベンジル、例えばヒドロキシ置換若しくはアミノ置換されたアルキル又はベンジルである。さらなる実施態様において、R^a、及びR^bは、独立してベンジル、又は置換されたアルキルである。さらなる実施態様において、R^yは、アルキル、及びヒドロキシアルキルからなる群から選択される。特定の実施態様において、R^yは、-C（CH₃）₂CH₂OHである。 In another embodiment, the compounds provided herein have the formula:

A compound of
In the formula, R ^a , R ^b , and R ^y are as defined in formula IIa or IIb. In certain embodiments, R ^a is hydrogen, R ^b is —CH ₂ —C ₆ H ₅ , and R ^y is —C (CH ₃ ) ₂ CH ₂ OH. In certain embodiments according to this paragraph, R ^y is substituted alkyl, such as hydroxyalkyl or aminoalkyl; and R ^a and R ^b are independently hydrogen, alkyl, substituted alkyl , Benzyl, or substituted benzyl, such as hydroxy-substituted or amino-substituted alkyl or benzyl. In another embodiment, R ^y is -OR ^c , -C (R ^c ) ₃ , or -NHR ^c , wherein each R ^c is independently alkyl, substituted alkyl, aryl, or Substituted aryl, such as hydroxy-substituted or amino-substituted alkyl or aryl; and R ^a and R ^b are independently hydrogen, alkyl, substituted alkyl, benzyl, or substituted benzyl, such as hydroxy Substituted or amino substituted alkyl or benzyl. In a further embodiment, R ^a and R ^b are independently benzyl, or substituted alkyl. In a further embodiment, R ^y is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, R ^y is —C (CH ₃ ) ₂ CH ₂ OH.

の化合物であり、
式中、Xは、ハロゲンであり、R^a、R^b、及びR^yは、式IIa、又はIIbにおいて定義したとおりであり、かつR²、及びR³は、それぞれ独立して、H、直鎖、分枝、又は環状のアルキル；アシル（低級アシルを含む）；CO-アルキル、CO-アリール、CO-アルコキシアルキル、CO-アリールオキシアルキル、CO-置換されたアリール、メタンスルホニルを含むアルキル又はアリールアルキルスルホニルなどのスルホナートエステル、及びベンジルであって、式中フェニル基は、任意に置換されており；アルキルスルホニル、アリールスルホニル、アラルキルスルホニル、リン脂質などの脂質；アミノ酸；及びアミノ酸残基、炭水化物；ペプチド；コレステロール；例えばインビボで投与されたときに、R²、及び／又はR³が独立してH、又はホスフェート（モノ、ジ、又はトリホスフェートを含む）である化合物を提供することができるその他の医薬として許容し得る脱離基である。R^Lは、水素、又は当業者に公知の任意の親油性基である。特定の実施態様において、R²、及びR³は、それぞれ水素であり、R^aは、水素であり、R^bは、-CH₂-C₆H₅であり、かつR^yは、-C(CH₃)₂CH₂OHである。特定の実施態様において、前記親油基は、アルキル、アルケニル、シクロアルキル、アリール、ヘテロアリール、アリールアルキル、及びヘテロアリール-アルキルから選択される。このパラグラフに従った特定の実施態様において、Xは、フルオロであり、R^Lは、水素であり、R²、及びR³は、それぞれHであり、R^yは、置換されたアルキル、例えばヒドロキシアルキル、又はアミノアルキルであり；かつR^a、及びR^bは、独立して水素、アルキル、置換されたアルキル、ベンジル、又は置換されたベンジル、例えばヒドロキシ置換若しくはアミノ置換されたアルキル又はベンジルである。別の実施態様において、Xは、フルオロであり、R^Lは、水素であり、R²、及びR³は、それぞれHであり、R^yは、-OR^c、-C(R^c)₃、又は-NHR^cであり、式中それぞれのR^cは、独立してアルキル、置換されたアルキル、アリール、又は置換されたアリール、例えばヒドロキシ置換若しくはアミノ置換されたアルキル又はアリールであり；かつR^a、及びR^bは、独立して水素、アルキル、置換されたアルキル、ベンジル、又は置換されたベンジル、例えばヒドロキシ置換若しくはアミノ置換されたアルキル又はベンジルである。さらなる実施態様において、Xは、フルオロであり、R^Lは、水素であり、R²、及びR³は、それぞれHであり、R^a、及びR^bは、独立してベンジル、又は置換されたアルキルである。さらなる実施態様において、Xは、フルオロであり、R^Lは、水素であり、R²、及びR³は、それぞれHであり、R^yは、アルキル、及びヒドロキシアルキルからなる群から選択される。特定の実施態様において、Xは、フルオロであり、R^Lは、水素であり、R²、及びR³は、それぞれHであり、R^yは、-C(CH₃)₂CH₂OHである。 In another embodiment, the compounds provided herein have the formula:

A compound of
Wherein X is halogen, R ^a , R ^b , and R ^y are as defined in formula IIa or IIb, and R ² and R ³ are each independently H, straight Chain, branched, or cyclic alkyl; acyl (including lower acyl); CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkyl including methanesulfonyl, or Sulfonate esters such as arylalkylsulfonyl, and benzyl, wherein the phenyl group is optionally substituted; lipids such as alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, phospholipid; amino acids; and amino acid residues; Carbohydrate; peptide; cholesterol; for example, when administered in vivo, R ² and / or R ³ are independently H, or phosphate (mono, di) Or any other pharmaceutically acceptable leaving group that can provide a compound that includes triphosphate. R ^L is hydrogen or any lipophilic group known to those skilled in the art. In certain embodiments, R ² and R ³ are each hydrogen, R ^a is hydrogen, R ^b is —CH ₂ —C ₆ H ₅ , and R ^y is —C ( CH ₃ ) ₂ CH ₂ OH. In certain embodiments, the lipophilic group is selected from alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, arylalkyl, and heteroaryl-alkyl. In certain embodiments according to this paragraph, X is fluoro, R ^L is hydrogen, R ² and R ³ are each H, and R ^y is substituted alkyl, such as hydroxy Alkyl, or aminoalkyl; and R ^a and R ^b are independently hydrogen, alkyl, substituted alkyl, benzyl, or substituted benzyl, eg, hydroxy-substituted or amino-substituted alkyl or benzyl . In another embodiment, X is fluoro, R ^L is hydrogen, R ² and R ³ are each H, and R ^y is —OR ^c , —C (R ^c ) ₃ , Or —NHR ^c , wherein each R ^c is independently alkyl, substituted alkyl, aryl, or substituted aryl, such as hydroxy-substituted or amino-substituted alkyl or aryl; and R ^a , And R ^b are independently hydrogen, alkyl, substituted alkyl, benzyl, or substituted benzyl, such as hydroxy- or amino-substituted alkyl or benzyl. In a further embodiment, X is fluoro, R ^L is hydrogen, R ² and R ³ are each H, and R ^a and R ^b are independently benzyl or substituted. Alkyl. In a further embodiment, X is fluoro, R ^L is hydrogen, R ² and R ³ are each H, and R ^y is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, X is fluoro, R ^L is hydrogen, R ² and R ³ are each H, and R ^y is —C (CH ₃ ) ₂ CH ₂ OH. .

の化合物であり、式中、R^a、R^b、及びR^yは、式IIa、又はIIbにおいて定義したとおりである。特定の実施態様において、R^yは、置換されたアルキル、例えばヒドロキシアルキル、又はアミノアルキルであり；かつR^a、及びR^bは、独立して水素、アルキル、置換されたアルキル、ベンジル、又は置換されたベンジル、例えばヒドロキシ置換若しくはアミノ置換されたアルキル又はベンジルである。別の実施態様において、R^yは、-OR^c、-C(R^c)₃、又は-NHR^cであり、式中それぞれのR^cは、独立してアルキル、置換されたアルキル、アリール、又は置換されたアリール、例えばヒドロキシ置換若しくはアミノ置換されたアルキル又はアリールであり；かつR^a、及びR^bは、独立して水素、アルキル、置換されたアルキル、ベンジル、又は置換されたベンジル、例えばヒドロキシ置換若しくはアミノ置換されたアルキル又はベンジルである。さらなる実施態様において、R^a、及びR^bは、独立してベンジル、又は置換されたアルキルである。さらなる実施態様において、R^yは、アルキル、及びヒドロキシアルキルからなる群から選択される。特定の実施態様において、R^aは、水素であり、R^bは、-CH₂-C₆H₅であり、かつR^yは、-C(CH₃)₂CH₂OHである。 In another embodiment, the compounds provided herein have the formula:

Wherein R ^a , R ^b , and R ^y are as defined in formula IIa or IIb. In certain embodiments, R ^y is substituted alkyl, such as hydroxyalkyl, or aminoalkyl; and R ^a and R ^b are independently hydrogen, alkyl, substituted alkyl, benzyl, or substituted Benzyl, eg hydroxy- or amino-substituted alkyl or benzyl. In another embodiment, R ^y is -OR ^c , -C (R ^c ) ₃ , or -NHR ^c , wherein each R ^c is independently alkyl, substituted alkyl, aryl, or Substituted aryl, such as hydroxy-substituted or amino-substituted alkyl or aryl; and R ^a and R ^b are independently hydrogen, alkyl, substituted alkyl, benzyl, or substituted benzyl, such as hydroxy Substituted or amino substituted alkyl or benzyl. In a further embodiment, R ^a and R ^b are independently benzyl, or substituted alkyl. In a further embodiment, R ^y is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, R ^a is hydrogen, R ^b is —CH ₂ —C ₆ H ₅ , and R ^y is —C (CH ₃ ) ₂ CH ₂ OH.

の化合物であり、 In another embodiment, the compounds provided herein have the formula:

A compound of

In the formula, R ^a , R ^b , and R ^y are as defined in formula IIa or IIb. In certain embodiments, R ^y is substituted alkyl, such as hydroxyalkyl, or aminoalkyl; and R ^a and R ^b are independently hydrogen, alkyl, substituted alkyl, benzyl, or substituted Benzyl, eg hydroxy- or amino-substituted alkyl or benzyl. In another embodiment, R ^y is -OR ^c , -C (R ^c ) ₃ , or -NHR ^c , wherein each R ^c is independently alkyl, substituted alkyl, aryl, or Substituted aryl, such as hydroxy-substituted or amino-substituted alkyl or aryl; and R ^a and R ^b are independently hydrogen, alkyl, substituted alkyl, benzyl, or substituted benzyl, such as hydroxy Substituted or amino substituted alkyl or benzyl. In a further embodiment, R ^a and R ^b are independently benzyl, or substituted alkyl. In a further embodiment, R ^y is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, R ^a is hydrogen, R ^b is —CH ₂ —C ₆ H ₅ , and R ^y is —C (CH ₃ ) ₂ CH ₂ OH.

の化合物であり、 In another embodiment, the compounds provided herein have the formula:

A compound of

In the formula, R ^a , R ^b , and R ^y are as defined in formula IIa or IIb. In certain embodiments, R ^y is substituted alkyl, such as hydroxyalkyl, or aminoalkyl; and R ^a and R ^b are independently hydrogen, alkyl, substituted alkyl, benzyl, or substituted Benzyl, eg hydroxy- or amino-substituted alkyl or benzyl. In another embodiment, R ^y is -OR ^c , -C (R ^c ) ₃ , or -NHR ^c , wherein each R ^c is independently alkyl, substituted alkyl, aryl, or Substituted aryl, such as hydroxy-substituted or amino-substituted alkyl or aryl; and R ^a and R ^b are independently hydrogen, alkyl, substituted alkyl, benzyl, or substituted benzyl, such as hydroxy Substituted or amino substituted alkyl or benzyl. In a further embodiment, R ^a and R ^b are independently benzyl, or substituted alkyl. In a further embodiment, R ^y is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, R ^a is hydrogen, R ^b is —CH ₂ —C ₆ H ₅ , and R ^y is —C (CH ₃ ) ₂ CH ₂ OH.

の化合物であり、 In another embodiment, the compounds provided herein have the formula:

A compound of

In the formula, R ^a , R ^b , and R ^y are as defined in formula IIa or IIb. In certain embodiments, R ^y is substituted alkyl, such as hydroxyalkyl, or aminoalkyl; and R ^a and R ^b are independently hydrogen, alkyl, substituted alkyl, benzyl, or substituted Benzyl, eg hydroxy- or amino-substituted alkyl or benzyl. In another embodiment, R ^y is -OR ^c , -C (R ^c ) ₃ , or -NHR ^c , wherein each R ^c is independently alkyl, substituted alkyl, aryl, or Substituted aryl, such as hydroxy-substituted or amino-substituted alkyl or aryl; and R ^a and R ^b are independently hydrogen, alkyl, substituted alkyl, benzyl, or substituted benzyl, such as hydroxy Substituted or amino substituted alkyl or benzyl. In a further embodiment, R ^a and R ^b are independently benzyl, or substituted alkyl. In a further embodiment, R ^y is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, R ^a is hydrogen, R ^b is —CH ₂ —C ₆ H ₅ , and R ^y is —C (CH ₃ ) ₂ CH ₂ OH.

の化合物であり、式中、R^a、R^b、及びR^yは、式IIa、又はIIbにおいて定義したとおりである。 In another embodiment, the compounds provided herein have the formula:

Wherein R ^a , R ^b , and R ^y are as defined in formula IIa or IIb.

R ^L is hydrogen or any lipophilic group known to those skilled in the art. In certain embodiments, R ^a is hydrogen, R ^b is —CH ₂ —C ₆ H ₅ , and R ^y is —C (CH ₃ ) ₂ CH ₂ OH. In certain embodiments, the lipophilic group is selected from alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, arylalkyl, and heteroaryl-alkyl. In certain embodiments according to this paragraph, R ^y is substituted alkyl, such as hydroxyalkyl or aminoalkyl; and R ^a and R ^b are independently hydrogen, alkyl, substituted alkyl , Benzyl, or substituted benzyl, such as hydroxy-substituted or amino-substituted alkyl or benzyl. In another embodiment, R ^y is —C (R ^c ) ₃ , or —NHR ^c , wherein each R ^c is independently alkyl, substituted alkyl, aryl, or substituted aryl. , for example, be a hydroxy-substituted or amino-substituted alkyl or aryl; and R ^a, and R ^b are independently hydrogen, alkyl, substituted alkyl, benzyl, or substituted benzyl, such as hydroxy-substituted or amino-substituted Alkyl or benzyl. In a further embodiment, R ^a and R ^b are independently benzyl, or substituted alkyl. In a further embodiment, R ^y is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, R ^y is —C (CH ₃ ) ₂ CH ₂ OH.

の化合物であり、
式中、変数は、上記の通りである。 In another embodiment, the compounds provided herein have the formula:

A compound of
In the formula, the variables are as described above.

の化合物であり、
式中、変数は、上記の通りである。 In another embodiment, the compounds provided herein have the formula:

A compound of
In the formula, the variables are as described above.

In one embodiment, R ¹ is a natural nucleoside. In one embodiment, R ¹ is a 2 ′ or 3 ′ prodrug of a biologically active 1 ′, 2 ′, 3 ′, or 4′C branched β-D or β-L nucleoside. As used herein, a 1 ', 2', 3 ', or 4'C-branch has a nucleoside having an additional unnatural substituent at the 1', 2 ', 3', or 4 'position including. (Ie, the carbon is attached to four non-hydrogen substituents). As used herein, the term 2′-prodrug includes, but is not limited to, acyl, and in one embodiment, a natural or synthetic D or L amino acid, in one embodiment, an L amino acid. Includes 1 ′, 2 ′, 3 ′, or 4 ′ C-branched-β-D or β-L nucleosides that have a biologically cleavable moiety at the 2′-position. As used herein, the term 3′-prodrug includes acyl, in one embodiment, a natural or synthetic D or L amino acid, in one embodiment, including but not limited to an L amino acid, 3 Includes 1 ', 2', 3 ', or 4'C-branched-β-D, or β-L nucleosides with a biologically cleavable moiety in the' -position. In one embodiment, the amino acid is valine.

  Examples of prodrugs (eg, can be further derivatized as described herein to include a phosphoramidate or phosphonoamidate moiety at the 5 ′ position) include: β-D -2'-C-methyl-cytidine 2'-L-valine ester; β-D-2'-C-methyl-thymidine 2'-L-valine ester; β-D-2'-C-methyl- 2'-L-valine ester of adenosine; 2'-L-valine ester of β-D-2'-C-methyl-guanosine; 2'- of β-D-2'-C-methyl-5-fluorocytidine L-valine ester; 2'-L-valine ester of β-D-2'-C-methyl-uridine; 2'-acetyl ester of β-D-2'-C-methyl-cytidine; β-D-2 2'-acetyl ester of '-C-methyl-thymidine; 2'-acetyl ester of β-D-2'-C-methyl-adenosine; 2'-acetyl of β-D-2'-C-methyl-guanosine Esters; 2'-acetyl esters of β-D-2'-C-methyl-5fluorocytidine; and β-D-2 ' A 2′-ester of —C-methyl- (cytidine, 5-fluorocytidine, guanosine, uridine, adenosine, or thymidine), wherein (i) the 2 ′ ester is an amino acid ester; or (ii) 2 'Ester is an alkyl or aryl ester.

  Further examples of prodrugs include 3′-L-valine ester of β-D-2′-C-methyl-cytidine; 3′-L-valine ester of β-D-2′-C-methyl-thymidine; β-D-2'-C-methyl-adenosine 3'-L-valine ester; β-D-2'-C-methyl-guanosine 3'-L-valine ester; β-D-2'-C 3'-L-valine ester of -methyl-5-fluorocytidine; 3'-L-valine ester of β-D-2'-C-methyl-uridine; of β-D-2'-C-methyl-cytidine 3'-acetyl ester; 3'-acetyl ester of β-D-2'-C-methyl-thymidine; 3'-acetyl ester of β-D-2'-C-methyl-adenosine; β-D-2 ' 3'-acetyl ester of -C-methyl-guanosine; 3'-acetyl ester of β-D-2'-C-methyl-5fluorocytidine; and β-D-2'-C-methyl- (cytidine, 5 -Fluorocytidine, guanosine, uridine, adenosine, or thymidine), wherein (i) the 3 ′ ester is Whether the Roh ester; or (ii) 3 'ester is an alkyl or aryl ester.

  Further examples of prodrugs include: 2 ′, 3′-L-divaline ester of β-D-2′-C-methyl-cytidine (Gival-2′-Me-L-dC); -2 ', 3'-L-divaline ester of D-2'-C-methyl-thymidine; 2', 3'-L-divaline ester of β-D-2'-C-methyladenosine; 2 ', 3'-L-divaline ester of D-2'-C-methylguanosine; 2', 3'-L-divaline ester of β-D-2'-C-methyl-5-fluorocytidine; β-D-2′-C-methyluridine 2 ′, 3′-L-divaline ester; β-D-2′-C-methylcytidine 2 ′, 3′-diacetyl ester; β-D-2 '-C-methylthymidine 2', 3'-diacetyl ester; β-D-2'-C-methyladenosine 2 ', 3'-diacetyl ester; β-D-2'-C-methylguanosine 2 ', 3'-diacetyl ester; 2', 3'-diacetyl ester of β-D-2'-C-methyl-5fluorocytidine; and β-D-2'-C-methyl- (cytidine, 5-fluoro Cytidine, guanosine, uridine, (A) the 2 'ester is an amino acid ester and the 3'-ester is an alkyl or aryl ester; (ii) both The ester is an amino acid ester; (iii) both esters are independently alkyl or aryl esters; or (iv) the 2 ′ ester is an alkyl or aryl ester, and the 3′-ester is An amino acid ester.

であり、
式中
Baseは、本明細書で定義したとおりの天然若しくは非天然のプリン又はピリミジン塩基であり；
R⁶は、水素、ヒドロキシ、アルキル、アルケニル、アルキニル、アジド、シアノ、Br-ビニル、アルコキシ、アシルオキシ、アルコキシカルボニル、アルケニルオキシ、ハロ、NO₂、又はNR^6aR^6bであり；
R^6a、及びR^6bは、それぞれ独立して水素、アルキル、アルケニル、アルキニル、シクロアルキル、アシル、アリール、ヘテロアリール、又はヘテロシクリルであり；
R⁷、R⁹、R⁸、及びR¹⁰は、以下の通りに選択され：
i）R⁷、及びR⁹は、それぞれ独立して、水素、OR^7a、ヒドロキシ、アルキル、アルケニル、アルキニル、アジド、シアノ、Br-ビニル、アルキルオキシカルボニル、アシルオキシ、ハロ、NO₂、若しくはNR^6aR^6bであるか
ii）R⁸、及びR¹⁰は、それぞれ独立してH、アルキル、又はハロであるか；又は、
iii）それぞれのR⁷及びR⁹、R⁷及びR¹⁰、R⁸及びR⁹、又はR⁸及びR¹⁰は、共に二重結合を形成し；
R^7aは、H；直鎖、分枝、又は環状のアルキル（低級アルキルを含む）；アシル（低級アシルを含む）；CO-アルキル、CO-アリール、CO-アルコキシアルキル、CO-アリールオキシアルキル、CO-置換されたアリール、メタンスルホニルを含むアルキル又はアリールアルキルスルホニルなどのスルホナートエステル、及びベンジルであって、式中フェニル基は、本明細書に示したアリールの定義に記載されているように、1つ以上の置換基で任意に置換されており；アルキルスルホニル、アリールスルホニル、アリールアルキルスルホニル、リン脂質を含む脂質；アミノ酸；及びアミノ酸残基、炭水化物；ペプチド；コレステロール；又は例えば、インビボで投与されたときに、例えば、R^7aがH、若しくはホスフェート（モノ、ジ、又はトリホスフェートを含む）である化合物を提供することができるその他の医薬として許容し得る脱離基であり；式中、一つの実施態様において、R^7aは、ホスフェート（モノ、ジ、若しくはトリホスフェート、又は安定化されたホスフェートプロドラッグを含む）ではないか、又は2つのR^7a基は、アルキル、エステル、若しくはカルバメート結合によって環状基を形態するように連結されており；かつ
Xは、O、S、SO₂、又はCH₂である。 In one embodiment, R ¹ is:

And
In the formula
Base is a natural or non-natural purine or pyrimidine base as defined herein;
R ⁶ is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, azide, cyano, Br-vinyl, alkoxy, acyloxy, alkoxycarbonyl, alkenyloxy, halo, NO ₂ , or NR ^6a R ^6b ;
R ^6a and R ^6b are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, aryl, heteroaryl, or heterocyclyl;
R ⁷ , R ⁹ , R ⁸ , and R ¹⁰ are selected as follows:
i) R ⁷ and R ⁹ are each independently hydrogen, OR ^7a , hydroxy, alkyl, alkenyl, alkynyl, azide, cyano, Br-vinyl, alkyloxycarbonyl, acyloxy, halo, NO ₂ , or NR ^{6a Is} R ^6b
ii) R ⁸ and R ¹⁰ are each independently H, alkyl, or halo; or
iii) each R ⁷ and R ⁹ , R ⁷ and R ¹⁰ , R ⁸ and R ⁹ , or R ⁸ and R ¹⁰ together form a double bond;
R ^7a is H; linear, branched, or cyclic alkyl (including lower alkyl); acyl (including lower acyl); CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonate esters such as alkyl containing methanesulfonyl or arylalkylsulfonyl, and benzyl, wherein the phenyl group is as described in the definition of aryl given herein. , Optionally substituted with one or more substituents; lipids including alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, phospholipids; amino acids; and amino acid residues, carbohydrates; peptides; cholesterol; or administered in vivo, for example when it is, for example, R ^7a is H, or phosphate (mono-, di-, or triphosphate It is possible to provide a compound which is included) is a leaving group other pharmaceutically acceptable; wherein, in one embodiment, R ^7a is phosphate (mono-, di-, or triphosphate, or a stabilized Or two R ^7a groups are linked to form a cyclic group by alkyl, ester, or carbamate linkages; and
X is O, S, SO ₂ or CH ₂ .

を有し、 In one embodiment, R ¹ is of the formula:

Have

Wherein R ² and R ³ are each independently H; linear, branched, or cyclic alkyl; acyl (including lower acyl); CO-alkyl, CO-aryl, CO-alkoxyalkyl, Sulfonate esters such as CO-aryloxyalkyl, CO-substituted aryl, alkyl including methanesulfonyl or arylalkylsulfonyl, and benzyl, wherein the phenyl group is optionally substituted; alkylsulfonyl, arylsulfonyl , Arylalkylsulfonyl, lipids such as phospholipids; amino acids; and amino acid residues, carbohydrates; peptides; cholesterol; or, for example, when administered in vivo, R ² and / or R ³ are independently H, Or a compound that is phosphate (including mono, di, or triphosphate) Are other pharmaceutically acceptable leaving groups; or R ² and R ³ are linked to form a cyclic group by an alkyl, ester, or carbamate bond;

Where Y ¹ is hydrogen, bromo, chloro, fluoro, iodo, CN, OH, OR ⁴ , NH ₂ , NHR ⁴ , NR ⁴ R ⁵ , SH, or SR ⁴ ;

X ¹ is linear, branched or cyclic optionally substituted alkyl, CH ₃ , CF ₃ , C (Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C (Y ³ ) ₂ C (Y ³ ) ₃ , CH ₂ OH, optionally substituted alkenyl, optionally substituted alkynyl, COOH, COOR ⁴ , COO-alkyl, COO-aryl , ^{_{CO-O-alkoxyalkyl, CONH 2, CONHR 4, CON}} (R 4) 2, chloro, bromo, fluoro, _{iodo, CN, N 3, OH,} OR 4, NH 2, NHR 4, NR 4 R 5, SH Or SR ⁵ ; and

X ² is H, linear, branched, or cyclic optionally substituted alkyl, CH ₃ , CF ₃ , C (Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C (Y ³ ) ₂ C (Y ³ ) ₃ , CH ₂ OH, optionally substituted alkenyl, optionally substituted alkynyl, COOH, COOR ⁴ , COO-alkyl, COO - aryl, ^{_{CO-O-alkoxyalkyl, CONH 2, CONHR 4, CON}} (R 4) 2, chloro, bromo, fluoro, _{iodo, CN, N 3, OH,} OR 4, NH 2, NHR 4, NR 4 R 5 , SH, or SR ⁵ ; and

Each Y ³ is independently H, F, Cl, Br, or I;

Each R ⁴ and R ⁵ is independently hydrogen, acyl (including lower acyl), alkyl (including but not limited to methyl, ethyl, propyl, and cyclopropyl), lower alkyl, alkenyl, alkynyl, Or cycloalkyl.

In the embodiment described herein, R ^2, and / or R ^3, for example, when administered in vivo, R ^2, and / or R ³ is independently H, or phosphates (mono-, di-, Or a pharmaceutically acceptable leaving group that can provide a compound that comprises triphosphate).

In another embodiment, each R ² and R ³ is independently hydrogen or acyl. In another embodiment, R ² and R ³ are linked to form a cyclic group by an alkyl, ester, or carbamate bond.

であり、 In another embodiment, R ¹ is:

And

In the formula, R ² , R ³ , Y ¹ , Y ³ , X ¹ , and X ² are as defined in Formula XIII.

であり、
式中、Baseは、

からなる群から選択され、 In one embodiment, R ¹ is:

And
Where Base is

Selected from the group consisting of

Wherein each W ¹ , W ² , W ³ , and W ⁴ is independently N, CH, CF, CI, CBr, CCl, CCN, CCH ₃ , CCF ₃ , CCH ₂ CH ₃ , CC (O ) NH ₂ , CC (O) NHR ⁴ , CC (O) N (R ⁴ ) ₂ , CC (O) OH, CC (O) OR ⁴ , or CX ³ ;

Each W * is independently O, S, NH, or NR ⁴ ;

X is O, S, SO ₂ , CH ₂ , CH ₂ OH, CHF, CF ₂ , C (Y ³ ) ₂ , CHCN, C (CN) ₂ , CHR ⁴ , or C (R ⁴ ) ₂ ;

X * is CH, CF, CY ³ , or CR ⁴ ;

X ² is H, linear, branched, or cyclic optionally substituted alkyl, CH ₃ , CF ₃ , C (Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C (Y ³ ) ₂ C (Y ³ ) ₃ , CH ₂ OH, optionally substituted alkenyl, optionally substituted alkynyl, COOH, COOR ⁴ , COO-alkyl, COO - aryl, ^{_{CO-O-alkoxyalkyl, CONH 2, CONHR 4, CON}} (R 4) 2, chloro, bromo, fluoro, _{iodo, CN, N 3, OH,} OR 4, NH 2, NHR 4, NR 4 R 5 , SH, or SR ⁵ ;

Each X ³ is independently a linear, branched, or cyclic optionally substituted alkyl (including lower alkyl), CH ₃ , CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N (CH ₃ ) ₂ , CH ₂ OH, halogenated alkyl (including halogenated lower alkyl), CF ₃ , C (Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C (Y ³ ) ₂ C (Y ³ ) ₃ , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl , Haloalkynyl, N ₃ , CN, -C (O) OH, -C (O) OR ⁴ , -C (O) O (lower alkyl), -C (O) NH ₂ , -C (O) NHR ⁴ , -C (O) NH (lower alkyl), -C (O) N (R ⁴ ) ₂ , -C (O) N (lower alkyl) ₂ , OH, OR ⁴ , -O (acyl), -O ( Lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), -O (alkynyl), -O (arylalkyl), -O (cycloalkyl), -S (acyl),- S (lower acyl), -S (R ⁴ ), -S (Lower alkyl), - S (alkenyl), - S (alkynyl), - S (arylalkyl), - S (cycloalkyl), chloro, bromo, fluoro, iodo, NH _2, -NH (lower alkyl), - NHR ⁴ , -NR ⁴ R ⁵ , -NH (acyl), -N (lower alkyl) ₂ , -NH (alkenyl), -NH (alkynyl), -NH (arylalkyl), -NH (cycloalkyl),- N (acyl) ₂ ;

Each Y is independently H, optionally substituted lower alkyl, cycloalkyl, alkenyl, _{alkynyl, CH 2 OH, CH 2 NH} 2, CH 2 NHCH 3, CH 2 N (CH 3) 2, CH 2 F, CH ₂ Cl, CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ CF ₂ CF ₃ , CH ₂ CO ₂ R, (CH ₂ ) _m COOH, (CH ₂ ) _m C00R, (CH ₂ ) _m CONH _2, selected from the group consisting of (CH _{²⁾ m} CONR _2, and (CH _{2) m} C0NHR;

  Where R is H, alkyl, or acyl;

Y ¹ is hydrogen, bromo, chloro, fluoro, iodo, CN, OH, OR ⁴ , NH ₂ , NHR ⁴ , NR ⁴ R ⁵ , SH, or SR ⁴ ;

Each Y ² is independently O, S, NH, or NR ⁴ ;

Each Y ³ is independently H, F, Cl, Br, or I;

Each R ⁴ and R ⁵ is independently hydrogen, acyl (including lower acyl), alkyl (including but not limited to methyl, ethyl, propyl, and cyclopropyl), lower alkyl, alkenyl, alkynyl, Or cycloalkyl;

Each R ⁶ is independently an optionally substituted alkyl (including lower alkyl), CH ₃ , CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N (CH ₃ ) ₂ , CH ₂ OH, halogenated alkyl (including halogenated lower alkyl), CF ₃ , C (Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C (Y ³ ) ₂ C (Y ³ ) ₃ , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, —CH ₂ C ( O) OH, —CH ₂ C (O) OR ⁴ , —CH ₂ C (O) O (lower alkyl), —CH ₂ C (O) NH ₂ , —CH ₂ C (O) NHR ⁴ , —CH ₂ C (O) NH (lower alkyl), —CH ₂ C (O) N (R ⁴ ) ₂ , —CH ₂ C (O) N (lower alkyl) ₂ , — (CH ₂ ) _m C (O) OH, -(CH ₂ ) _m C (O) OR ⁴ ,-(CH ₂ ) _m C (O) O (lower alkyl),-(CH ₂ ) _m C (O) NH ₂ ,-(CH ₂ ) _m C ( ^{O) NHR 4, - (CH} 2) m C (O) NH ( lower _{alkyl), - (CH 2) m} C (O) N (R 4) 2, - (CH 2) m C (O) N ( Grade _{alkyl) 2, -C (O) OH} , -C (O) OR 4, -C (O) O ( lower alkyl), - C (O) NH 2, -C (O) NHR 4, -C ( O) NH (lower alkyl), —C (O) N (R ⁴ ) ₂ , —C (O) N (lower alkyl) ₂ , or cyano;

Each R ⁷ is independently H, OH, OR ² , optionally substituted alkyl (including lower alkyl), CH ₃ , CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH _3, CH (including halogenated lower _{alkyl) 2 N (CH 3) 2} , CH 2 OH, halogenated ^{_{alkyl, CF 3, C (Y 3}} ) 3, 2-Br- ethyl, CH ₂ F , CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C (Y ³ ) ₂ C (Y ³ ) ₃ , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, halo Alkynyl, optionally substituted carbocyclic compounds (eg, 3-7 membered cyclic carbon), optionally substituted heterocycles (eg, 3-7 having one or more O, S, and / or N) Membered heterocyclic ring), optionally substituted heteroaryl (eg, 3-7 membered aromatic heterocycle having one or more O, S, and / or N), —CH ₂ C (O) OH, -CH ₂ C (O) OR ⁴ , -CH ₂ C (O) O (lower alkyl), -CH ₂ C _{(O) SH, -CH 2 C} (O) SR 4, -CH 2 C (O) S ( lower _{alkyl), - CH 2 C (O} ) NH 2, -CH 2 C (O) NHR 4, -CH ₂ C (O) NH (lower alkyl), -CH ₂ C (O) N (R ⁴ ) ₂ , -CH ₂ C (O) N (lower alkyl) ₂ ,-(CH ₂ ) _m C (O) OH ,-(CH ₂ ) _m C (O) OR ⁴ ,-(CH ₂ ) _m C (O) O (lower alkyl),-(CH ₂ ) _m C (O) SH,-(CH ₂ ) _m C ( O) SR ⁴ ,-(CH ₂ ) _m C (O) S (lower alkyl),-(CH ₂ ) _m C (O) NH ₂ ,-(CH ₂ ) _m C (O) NHR ⁴ ,-(CH ₂ ) _m C (O) NH (lower alkyl),-(CH ₂ ) _m C (O) N (R ⁴ ) ₂ ,-(CH ₂ ) _m C (O) N (lower alkyl) ₂ , -C ( O) OH, -C (O) OR ⁴ , -C (O) O (lower alkyl), -C (O) SH, -C (O) SR ⁴ , -C (O) S (lower alkyl),- _{C (O) NH 2, -C} (O) NHR 4, -C (O) NH ( lower alkyl), - C (O) N (R 4) 2, -C (O) N ( lower alkyl) _2, -O (acyl), -O (lower acyl), -O (R ⁴ ) -O (alkyl), -O (lower alkyl), -O (alkenyl), -O (alkynyl), -O (arylalkyl) , -O (cycloalkyl), -S (acyl), -S (lower acyl), -S (R ⁴ ), -S (lower alkyl), -S (ar Kenyir), - S (alkynyl), - S (arylalkyl), - S _{(cycloalkyl), NO 2, NH 2,} -NH ( lower ^{alkyl), - NHR 4, -NR 4} R 5, -NH ( acyl ), -N (lower alkyl) ₂ , -NH (alkenyl), -NH (alkynyl), -NH (arylalkyl), -NH (cycloalkyl), -N (acyl) ₂ , azide, cyano, SCN, OCN , NCO, or halo (fluoro, chloro, bromo, iodo);

Alternatively, R ⁶ and R ⁷ together are an optionally substituted carbocyclic compound (eg, 3-7 membered cyclic carbon), or an optionally substituted heterocycle (eg, one or more A spiro compound selected from the group consisting of 3-7 membered heterocyclic rings having O, S and / or N;

  Each m is independently O, 1, or 2.

である。 In one embodiment, the base is

It is.

である。 In one embodiment, the base is

It is.

であり、 In another embodiment, R ¹ is

And

Wherein each R ⁶ and R ⁷ is as defined in formula XX, XXI, or XXII above;

Wherein each R ⁸ and R ¹¹ is independently hydrogen, optionally substituted alkyl (including lower alkyl), CH ₃ , CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N (CH ₃ ) ₂ , CH ₂ OH, halogenated alkyl (including halogenated lower alkyl), CF ₃ , C (Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C (Y ³ ) ₂ C (Y ³ ) ₃ , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl , Haloalkynyl, -CH ₂ C (O) OH, -CH ₂ C (O) OR ⁴ , -CH ₂ C (O) O (lower alkyl), -CH ₂ C (O) NH ₂ , -CH ₂ C (O) NHR ⁴ , -CH ₂ C (O) NH (lower alkyl), -CH ₂ C (O) N (R ⁴ ) ₂ , -CH ₂ C (O) N (lower alkyl) ₂ ,-(CH ₂ ) _m C (O) OH,-(CH ₂ ) _m C (O) OR ⁴ ,-(CH ₂ ) _m C (O) O (lower alkyl),-(CH ₂ ) _m C (O) NH ₂ ,-(CH ₂ ) _m C (O) NHR ⁴ ,-(CH ₂ ) _m C (O) NH (lower alkyl),-(CH ₂ ) _m C (O) N (R ⁴ ) ₂ ,-(CH _{2) m C (O) N} ( lower _{Alkyl) 2, -C (O) OH} , -C (O) OR 4, -C (O) O ( lower alkyl), - C (O) NH 2, -C (O) NHR 4, -C (O ) NH (lower alkyl), —C (O) N (R ⁴ ) ₂ , —C (O) N (lower alkyl) ₂ , cyano, azide, NH-acyl, or N (acyl) ₂ ;

Each R ⁹ and R ¹⁰ is independently hydrogen, OH, OR ² , optionally substituted alkyl (including lower alkyl), CH ₃ , CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N (CH ₃ ) ₂ , CH ₂ OH, halogenated alkyl (including halogenated lower alkyl), CF ₃ , C (Y ³ ) ₃ , 2-Br-ethyl , CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C (Y ³ ) ₂ C (Y ³ ) ₃ , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted Alkynyl, haloalkynyl, optionally substituted carbocyclic compounds (eg, 3-7 membered cyclic carbon), optionally substituted heterocycles (eg, one or more O, S, and / or N 3-7 membered heterocyclic ring), optionally substituted heteroaryl having (e.g., 3-7 membered aromatic heterocyclic ring having one or more O, S, and / or N), - CH _{2 C (O) OH, -CH 2} C (O) OR 4, -CH 2 C (O) O ( lower A _{Kill), - CH 2 C (O} ) SH, -CH 2 C (O) SR 4, -CH 2 C (O) S ( lower _{alkyl), - CH 2 C (O} ) NH 2, -CH 2 C ( O) NHR ⁴ , -CH ₂ C (O) NH (lower alkyl), -CH ₂ C (O) N (R ⁴ ) ₂ , -CH ₂ C (O) N (lower alkyl) ₂ ,-(CH ₂ ) _m C (O) OH,-(CH ₂ ) _m C (O) OR ⁴ ,-(CH ₂ ) _m C (O) O (lower alkyl),-(CH ₂ ) _m C (O) SH,- (CH ₂ ) _m C (O) SR ⁴ ,-(CH ₂ ) _m C (O) S (lower alkyl),-(CH ₂ ) _m C (O) NH ₂ ,-(CH ₂ ) _m C (O ) NHR ⁴ ,-(CH ₂ ) _m C (O) NH (lower alkyl),-(CH ₂ ) _m C (O) N (R ⁴ ) ₂ ,-(CH ₂ ) _m C (O) N (lower Alkyl) ₂ , -C (O) OH, -C (O) OR ⁴ , -C (O) O (lower alkyl), -C (O) SH, -C (O) SR ⁴ , -C (O) S (lower alkyl), - C (O) NH 2, -C (O) NHR 4, -C (O) NH ( lower alkyl), - C (O) N (R 4) 2, -C (O) N (lower-alkyl) _2, -O (acyl), - O (lower ^{acyl), - O (R 4)} , - O ( alkyl), - O (lower alkyl), - O (alkenyl), - O (alkynyl ), - O (arylalkyl), - O (cycloalkyl), - S (acyl), - S (lower ^{acyl), - S (R 4)} , - S ( lower A Alkyl), - S (alkenyl), - S (alkynyl), - S (arylalkyl), - S _{(cycloalkyl), NO 2, NH 2,} -NH ( lower ^{alkyl), - NHR 4, -NR 4} R ⁵ , -NH (acyl), -N (lower alkyl) ₂ , -NH (alkenyl), -NH (alkynyl), -NH (arylalkyl), -NH (cycloalkyl), -N (acyl) ₂ , azide , Cyano, SCN, OCN, NCO, or halo (fluoro, chloro, bromo, iodo);

  Each m is independently O, 1, or 2;

Alternatively, R ⁶ and R ¹⁰ , R ⁷ and R ⁹ , R ⁸ and R ⁷ , or R ⁹ and R ¹¹ together are optionally substituted carbocyclic compounds (eg, 3-7 membered cyclic A bridged compound selected from the group consisting of carbon), or an optionally substituted heterocycle (eg, a 3-7 membered heterocyclic ring having one or more O, S, and / or N) Can be formed; or

Alternatively, R ⁶ and R ⁷ , or R ⁹ and R ¹⁰ together are optionally substituted carbocyclic compounds (eg, 3-7 membered cyclic carbon) or optionally substituted heterocycles. Spiro compounds selected from the group consisting of rings (eg, 3-7 membered heterocyclic rings having one or more O, S, and / or N) can be formed.

であり、
式中、Base*は、本明細書で定義したとおりのプリン、又はピリミジン塩基であり； In another embodiment, R ¹ is:

And
In which Base * is a purine or pyrimidine base as defined herein;

Each R ¹² is independently substituted alkyl (including lower alkyl), CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N (CH ₃ ) ₂ , CH ₂ OH, halogenated alkyl (including halogenated lower alkyl), CF ₃ , C (Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C (Y ³ ) ₂ C (Y ³ ) ₃ , substituted alkenyl, haloalkenyl (but not Br-vinyl), substituted alkynyl, haloalkynyl, —CH ₂ C (O) OH, — CH ₂ C (O) OR ⁴ , -CH ₂ C (O) O (lower alkyl), -CH ₂ C (O) NH ₂ , -CH ₂ C (O) NHR ⁴ , -CH ₂ C (O) NH (lower _{alkyl), - CH 2 C (O} ) N (R 4) 2, -CH 2 C (O) N ( lower _{alkyl) 2, - (CH 2)} m C (O) OH, - (CH 2) _m C (O) OR ⁴ ,-(CH ₂ ) _m C (O) O (lower alkyl),-(CH ₂ ) _m C (O) NH ₂ ,-(CH ₂ ) _m C (O) NHR ⁴ , _{- (CH 2) m C (} O) NH ( lower _{alkyl), - (CH 2) m} C (O) N (R 4) 2, - (CH 2) m C (O) N ( lower alkyl) _2, -C (O) OH, -C (O) OR ⁴ , -C (O) NH ₂ , -C (O) NHR ⁴ , -C (O) NH (lower alkyl), -C (O) N (R ⁴ ) ₂ , -C (O) N (lower alkyl) ₂ ;

Each R ¹³ is independently substituted alkyl (including lower alkyl), CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N (CH ₃ ) ₂ , CH ₂ OH, halogenated alkyl (including halogenated lower alkyl), CF ₃ , C (Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C (Y ³ ) ₂ C (Y ³ ) ₃ , substituted alkenyl, haloalkenyl (but not Br-vinyl), substituted alkynyl, haloalkynyl, optionally substituted carbocyclic compounds (eg , 3-7 membered cyclic carbon), optionally substituted heterocycle (eg, 3-7 membered heterocyclic ring having one or more O, S, and / or N), optionally substituted Heteroaryl (eg, a 3-7 membered aromatic heterocycle having one or more O, S, and / or N), —CH ₂ C (O) OH, —CH ₂ C (O) OR ⁴ , — CH ₂ C (O) O (lower alkyl), -CH ₂ C (O) SH, -CH ₂ C (O) SR ⁴ , -CH ₂ C (O) S (lower alkyl), --CH ₂ C (O) NH ₂ , --CH ₂ C (O) NHR ⁴ , --CH ₂ C (O) NH (lower alkyl), --CH ₂ C (O ) N (R ⁴ ) ₂ , -CH ₂ C (O) N (lower alkyl) ₂ ,-(CH ₂ ) _m C (O) OH,-(CH ₂ ) _m C (O) OR ⁴ ,-(CH ₂ ) _m C (O) O (lower alkyl),-(CH ₂ ) _m C (O) SH,-(CH ₂ ) _m C (O) SR ⁴ ,-(CH ₂ ) _m C (O) S ( lower _{alkyl), - (CH 2) m} C (O) NH 2, - (CH 2) m C (O) NHR 4, - (CH 2) m C (O) NH ( lower alkyl), - (CH ₂ ) _m C (O) N (R ⁴ ) ₂ ,-(CH ₂ ) _m C (O) N (lower alkyl) ₂ , -C (O) OH, -C (O) OR ⁴ , -C (O) SH, -C (O) SR ⁴ , -C (O) S (lower alkyl), -C (O) NH ₂ , -C (O) NHR ⁴ , -C (O) NH (lower alkyl), -C (O) N (R ⁴ ) ₂ , -C (O) N (lower alkyl) ₂ , -O (R ⁴ ), -O (alkynyl), -O (arylalkyl), -O (cycloalkyl),- S (acyl), -S (lower acyl), -S (R ⁴ ), -S (lower alkyl), -S (alkenyl), -S (alkynyl), -S (arylalkyl), -S (cycloalkyl) ), -NHR ⁴ , -NR ⁴ R ⁵ -NH (alkenyl), -NH (alkynyl), -NH (arylalkyl), -NH (cycloalkyl), SCN, OCN, NCO, or fluoro;

Alternatively, R ¹² and R ¹³ together are optionally substituted carbocyclic compounds (eg, 3-7 membered cyclic carbon), or optionally substituted heterocycles (eg, one or more A spiro compound selected from the group consisting of 3 to 7-membered heterocyclic rings having O, S and / or N;

R ² and R ³ are according to formula XII; and

  Each m is independently 0, 1, or 2.

であり、
式中、Base*は本明細書に記述したとおり、プリン、又はピリミジン塩基であり；かつ、 In another embodiment, R is:

And
Where Base * is a purine or pyrimidine base as described herein; and

Each R ⁸ and R ¹¹ is independently hydrogen, optionally substituted alkyl (including lower alkyl), CH ₃ , CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N (CH ₃ ) ₂ , CH ₂ OH, halogenated alkyl (including halogenated lower alkyl), CF ₃ , C (Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C (Y ³ ) ₂ C (Y ³ ) ₃ , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl , -CH ₂ C (O) OH, -CH ₂ C (O) OR ⁴ , -CH ₂ C (O) O (lower alkyl), -CH ₂ C (O) NH ₂ , -CH ₂ C (O) NHR ⁴ , —CH ₂ C (O) NH (lower alkyl), —CH ₂ C (O) N (R ⁴ ) ₂ , —CH ₂ C (O) N (lower alkyl) ₂ , — (CH ₂ ) _m C (O) OH,-(CH ₂ ) _m C (O) OR ⁴ ,-(CH ₂ ) _m C (O) O (lower alkyl),-(CH ₂ ) _m C (O) NH ₂ ,-( CH ₂ ) _m C (O) NHR ⁴ ,-(CH ₂ ) _m C (O) NH (lower alkyl),-(CH ₂ ) _m C (O) N (R ⁴ ) ₂ ,-(CH ₂ ) _m C (O) N (Lower Alky _{) 2, -C (O) OH} , -C (O) OR 4, -C (O) O ( lower alkyl), - C (O) NH 2, -C (O) NHR 4, -C (O) NH (lower alkyl), —C (O) N (R ⁴ ) ₂ , —C (O) N (lower alkyl) ₂ , cyano, NH-acyl, or N (acyl) ₂ ;

Each R ⁹ and R ¹⁰ is independently hydrogen, OH, OR ² , optionally substituted alkyl (including lower alkyl), CH ₃ , CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N (CH ₃ ) ₂ , CH ₂ OH, halogenated alkyl (including halogenated lower alkyl), CF ₃ , C (Y ³ ) ₃ , 2-Br-ethyl , CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C (Y ³ ) ₂ C (Y ³ ) ₃ , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted Alkynyl, haloalkynyl, optionally substituted carbocyclic compounds (eg, 3-7 membered cyclic carbon), optionally substituted heterocycles (eg, one or more O, S, and / or N Having a 3-7 membered heterocyclic ring), optionally substituted heteroaryl (eg, a 3-7 membered aromatic heterocycle having one or more O, S, and / or N), -CH _{2 C (O) OH, -CH} 2 C (O) OR 4, -CH 2 C (O) O ( lower A _{Kill), - CH 2 C (O} ) SH, -CH 2 C (O) SR 4, -CH 2 C (O) S ( lower _{alkyl), - CH 2 C (O} ) NH 2, -CH 2 C ( O) NHR ⁴ , -CH ₂ C (O) NH (lower alkyl), -CH ₂ C (O) N (R ⁴ ) ₂ , -CH ₂ C (O) N (lower alkyl) ₂ ,-(CH ₂ ) _m C (O) OH,-(CH ₂ ) _m C (O) OR ⁴ ,-(CH ₂ ) _m C (O) O (lower alkyl),-(CH ₂ ) _m C (O) SH,- (CH ₂ ) _m C (O) SR ⁴ ,-(CH ₂ ) _m C (O) S (lower alkyl),-(CH ₂ ) _m C (O) NH ₂ ,-(CH ₂ ) _m C (O ) NHR ⁴ ,-(CH ₂ ) _m C (O) NH (lower alkyl),-(CH ₂ ) _m C (O) N (R ⁴ ) ₂ ,-(CH ₂ ) _m C (O) N (lower Alkyl) ₂ , -C (O) OH, -C (O) OR ⁴ , -C (O) O (lower alkyl), -C (O) SH, -C (O) SR ⁴ , -C (O) S (lower alkyl), - C (O) NH 2, -C (O) NHR 4, -C (O) NH ( lower alkyl), - C (O) N (R 4) 2, -C (O) N (lower alkyl) ₂ , -O (acyl), -O (lower acyl), -O (R ⁴ ), -O (alkyl), -O (lower alkyl), -O (alkenyl), -O (alkynyl) ), - O (arylalkyl), - O (cycloalkyl), - S (acyl), - S (lower ^{acyl), - S (R 4)} , - S ( lower A Kill), - S (alkenyl), - S (alkynyl), - S (arylalkyl), - S _{(cycloalkyl), NO 2, NH 2,} -NH ( lower ^{alkyl), - NHR 4, -NR 4} R ⁵ , -NH (acyl), -N (lower alkyl) ₂ , -NH (alkenyl), -NH (alkynyl), -NH (arylalkyl), -NH (cycloalkyl), -N (acyl) ₂ , azide , Cyano, SCN, OCN, NCO, or halo (fluoro, chloro, bromo, iodo);

Each R ¹² is independently substituted alkyl (including lower alkyl), CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N (CH ₃ ) ₂ , CH ₂ OH, halogenated alkyl (including halogenated lower alkyl), CF ₃ , C (Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C (Y ³ ) ₂ C (Y ³ ) ₃ , substituted alkenyl, haloalkenyl (but not Br-vinyl), substituted alkynyl, haloalkynyl, —CH ₂ C (O) OH, — CH ₂ C (O) OR ⁴ , -CH ₂ C (O) O (lower alkyl), -CH ₂ C (O) NH ₂ , -CH ₂ C (O) NHR ⁴ , -CH ₂ C (O) NH (lower _{alkyl), - CH 2 C (O} ) N (R 4) 2, -CH 2 C (O) N ( lower _{alkyl) 2, - (CH 2)} m C (O) OH, - (CH 2) _m C (O) OR ⁴ ,-(CH ₂ ) _m C (O) O (lower alkyl),-(CH ₂ ) _m C (O) NH ₂ ,-(CH ₂ ) _m C (O) NHR ⁴ , _{- (CH 2) m C (} O) NH ( lower _{alkyl), - (CH 2) m} C (O) N (R 4) 2, - (CH 2) m C (O) N ( lower alkyl) _2, -C (O) OH, -C (O) OR ⁴ , -C (O) NH ₂ , -C (O) NHR ⁴ , -C (O) NH (lower alkyl), -C (O) N (R ⁴ ) ₂ , -C (O) N (lower alkyl) ₂ ;

  Each m is independently 0, 1, or 2;

Alternatively, R ⁸ and R ¹³ , R ⁹ and R ¹³ , R ⁹ and R ¹¹ , or R ¹⁰ and R ¹² together are optionally substituted carbocyclic compounds (eg, 3-7 membered cyclic A bridged compound selected from the group consisting of carbon), or an optionally substituted heterocycle (eg, a 3-7 membered heterocyclic ring having one or more O, S, and / or N) Can be formed; or

Alternatively, R ¹² and R ¹³ , or R ⁹ and R ¹⁰ together are optionally substituted carbocyclic compounds (eg, 3-7 membered cyclic carbon) or optionally substituted heterocycles ( For example, spiro compounds selected from the group consisting of 3 to 7 membered heterocyclic rings having one or more O, S, and / or N can be formed.

In one embodiment, R ¹ is:

  B is an optionally substituted carbocyclic compound (eg, 3-7 membered cyclic carbon), or an optionally substituted heterocycle (eg, 3 having one or more O, S, and / or N). A spiro compound selected from the group consisting of ˜7-membered heterocyclic rings;

Base is selected from the group consisting of:

Wherein each R ′, R ″, R ′ ″, and R ″ ″ is independently H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cyclo alkyl, Br @ - vinyl, -O- alkyl, O- alkenyl, O- alkynyl, O- aryl, O- arylalkyl, -O- acyl, O- cycloalkyl, NH _2, NH- alkyl, N- dialkyl, NH -Acyl, N-aryl, N-arylalkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S-cycloalkyl, S-arylalkyl, F, Cl, Br, I, CN _{, COOH, CONH 2, CO 2} - alkyl, CONH- alkyl, CON- _{dialkyl, OH, CF 3, CH 2} OH, (CH 2) m OH, (CH 2) m NH 2, (CH 2) m COOH, Selected from the group consisting of (CH ₂ ) _m CN, (CH ₂ ) _m NO ₂ , and (CH ₂ ) _m CONH ₂ ;

  m is 0 or 1;

  Each W is independently C—R ″, or N;

  T and V are independently CH or N;

Q is CH, —CCl, —CBr, —CF, —CI, —CCN, —C—COOH, —C—CONH ₂ , or N;

Q ₁ and Q ₂ are independently N or CR;

Q ₃ , Q ₄ , Q ₅ , and Q ₆ are independently N or CH; and

Its tautomeric form.

であり、 In another embodiment, R ¹ is:

And

G and E are independently CH ₃ , CH ₂ OH, CH ₂ F, CH ₂ N ₃ , CH ₂ CN, (CH ₂ ) _m COOH, (CH ₂ ) _m COOR, (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CONR ² , (CH ₂ ) _m CONHR, N ₃ , and N-acyl;

  m is 0 or l;

  R is H, alkyl, or acyl; and

  Base is as defined for formula (XIII).

  In one embodiment, at most one of G and E can further be hydrogen.

であり、 In another embodiment, R ¹ is:

And

Wherein M is selected from the group consisting of O, S, SO, and SO ₂ ; and Base is as defined for formula (XIII).

であり、 In certain embodiments, R ¹ is:

And

Where A is optionally substituted lower alkyl, cycloalkyl, alkenyl, alkynyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N (CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl, CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R, (CH ₂ ) _m COOH, (CH ₂ ) _m COOR, (CH ₂ ) _m CONH ₂ , selected from the group consisting of (CH ₂ ) _m CONR ² and (CH ₂ ) _m CONHR;

Y is, H, optionally substituted lower alkyl, cycloalkyl, alkenyl, _{alkynyl, CH 2 OH, CH 2 NH} 2, CH 2 NHCH 3, CH 2 N (CH 3) 2, CH 2 F, CH 2 Cl , CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R, (CH ₂ ) _m COOH, (CH ₂ ) _m COOR, (CH ₂ ) _m CONH ₂ It is selected from the group consisting of (CH _{²⁾ m} CONR _2, and (CH _{2) m} CONHR;

X is H, -OH, optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, -O-alkyl, -O-alkenyl, -O-alkynyl, -O-aryl, -O-arylalkyl, -O - cycloalkyl -, O-acyl, F, Cl, Br, I , CN, NC, SCN, OCN, NCO, NO 2, NH 2, N 3, NH- acyl, NH- alkyl, N- dialkyl, NH- Alkenyl, NH-alkynyl, NH-aryl, NH-arylalkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aryl, S-arylalkyl, S-acyl, S-cyclo alkyl, CO ₂ - alkyl, CONH- alkyl, CON- dialkyl, CONH- alkenyl, CONH- alkynyl, CONH- arylalkyl, CONH- _{cycloalkyl, CH 2 OH, CH 2 NH} 2, CH 2 NHCH 3, CH 2 N (CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl, CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R, (CH ₂ ) _m COOH, ( CH ₂ ) _m COOR , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CONR ₂ , (CH ₂ ) mC ₀ NHR, optionally substituted 3-7 membered carbocyclic compounds, alone or in combination, heteroatoms Independently selected from the group consisting of optionally substituted 3-7 membered heterocyclic rings having O, S, and / or N;

  m is 0 or 1;

R is H, alkyl, or acyl; and Base is an unnatural base selected from the following group:

Wherein each R ′, R ″, R ′ ″, and R ″ ″ is independently H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cyclo alkyl, Br @ - vinyl, -O- alkyl, O- alkenyl, O- alkynyl, O- aryl, O- arylalkyl, -O- acyl, O- cycloalkyl, NH _2, NH- alkyl, N- dialkyl, NH -Acyl, N-aryl, N-arylalkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S-cycloalkyl, S-arylalkyl, F, Cl, Br, I, CN _{, COOH, CONH 2, CO 2} - alkyl, CONH- alkyl, CON- _{dialkyl, OH, CF 3, CH 2} OH, (CH 2) m OH, (CH 2) m NH 2, (CH 2) m COOH, Selected from the group consisting of (CH ₂ ) _m CN, (CH ₂ ) _m NO ₂ , and (CH ₂ ) _m CONH ₂ ;

  m is 0 or 1;

  Each W is independently C—R ″, or N;

  T and V are independently CH or N;

Q is CH, —CCl, —CBr, —CF, —CI, —CCN, —C—COOH, —C—CONH ₂ , or N;

Q ₁ and Q ₂ are independently N or CR ""; and

Q ₃ , Q ₄ , Q ₅ and Q ₆ are independently N or CH;

However, in the bases (g) and (i), R ′, R ″ ″ is not H, OH, or NH ₂ ; and Q, T, V, Q ₂ , Q ₅ , and Q ₆ are N It is a condition that it is not.

In one embodiment, R ¹ is any natural or unnatural purine or pyrimidine base and 2 ′ of a 1 ′, 2 ′, 3 ′, or 4 ′ C-branched-β-D or β-L nucleoside. -(Alkyl or aryl) ester, or 3 '-(alkyl or aryl) ester. In one embodiment, R ¹ is a 2 ′ or 3 ′-(D or L) -amino acid ester of a 1 ′, 2 ′, 3 ′, or 4 ′ C-branched-β-D or β-L nucleoside. The amino acid is a natural or synthetic amino acid. In another embodiment, R ¹ is a 3′-D or L-amino acid ester of a 1 ′, 2 ′, 3 ′, or 4 ′ C-branched-β-D or β-L nucleoside, Amino acids are natural or synthetic amino acids. In one embodiment, the amino acid is an L-amino acid.

In one embodiment, the amino acid residue is of the formula C (O) C (R ¹¹ ) (R ¹² ) (NR ¹³ R ¹⁴ )

Wherein R ¹¹ is a side chain of an amino acid and R ¹¹ can optionally be attached to R ¹³ to form a ring structure; or alternatively, R ¹¹ is an alkyl An aryl, heteroaryl, or heterocyclic moiety;

R ¹² is hydrogen, alkyl (including lower alkyl), or aryl; and

R ¹³ and R ¹⁴ are independently hydrogen, acyl (including acyl derivatives attached to R ¹¹ ), or alkyl (including but not limited to methyl, ethyl, propyl, and cyclopropyl).

In another embodiment, at least one of R ² and R ³ is an amino acid residue. In one embodiment, at least one of R ² and R ³ is L-valinyl.

であり、
式中、R⁶、R⁷、R⁸、R⁹、R¹⁰、及びBase*は、式XXX、XXXI、XL、XLI、又はXLIIにおいて定義したとおりである。 In one embodiment, R ¹ is:

And
In the formula, R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , and Base * are as defined in the formula XXX, XXXI, XL, XLI, or XLII.

であり、
式中、R²、R³、R⁶、及びBase*は、式XXX、XXXI、XL、XLI、又はXLIIにおいて定義したとおりである。 In one embodiment, R ¹ is:

And
In the formula, R ² , R ³ , R ⁶ , and Base * are as defined in the formula XXX, XXXI, XL, XLI, or XLII.

であり、
式中、X¹、及びX²は、それぞれ独立して水素、アルキル、ハロ、又はアミノであり；Yは、水素、アミノ、アミノアルキル、アミノシクロアルキル、アルキル、シクロアルキル、ヒドロキシ、アルコキシ、シクロアルコキシ、SH、又はチオアルキルであり；Xは、O、又はSであり；かつ式中、R⁶、R⁷、R⁸、R⁹は、式XXX、XXXI、XL、XLI、又はXLIIにおいて定義したとおりである。 In one embodiment, R ¹ is:

And
Wherein X ¹ and X ² are each independently hydrogen, alkyl, halo, or amino; Y is hydrogen, amino, aminoalkyl, aminocycloalkyl, alkyl, cycloalkyl, hydroxy, alkoxy, cyclo Is alkoxy, SH, or thioalkyl; X is O, or S; and R ⁶ , R ⁷ , R ⁸ , R ⁹ are defined in formula XXX, XXXI, XL, XLI, or XLII It is as follows.

であり、
式中、X¹は、水素、アルキル、ハロ、又はアミノであり；Yは、水素、アミノ、アミノアルキル、アミノシクロアルキル、アルキル、シクロアルキル、ヒドロキシ、アルコキシ、シクロアルコキシ、SH、又はチオアルキルであり；Xは、O、又はSであり；かつ、式中、R⁶、R⁷、R⁸、R⁹は、式XXX、XXXI、XL、XLI、又はXLIIにおいて定義したとおりである。 In one embodiment, R ¹ is:

And
In which X ¹ is hydrogen, alkyl, halo, or amino; Y is hydrogen, amino, aminoalkyl, aminocycloalkyl, alkyl, cycloalkyl, hydroxy, alkoxy, cycloalkoxy, SH, or thioalkyl. X is O or S; and R ⁶ , R ⁷ , R ⁸ , R ⁹ are as defined in formula XXX, XXXI, XL, XLI, or XLII;

であり、
式中R²、R³、及びBase*は、式XIII、XXX、XXXI、XL、XLI、又はXLIIにおいて定義したとおりである。 In one embodiment, R ¹ is:

And
In the formula, R ² , R ³ and Base * are as defined in the formulas XIII, XXX, XXXI, XL, XLI or XLII.

であり、
式中、R²、R³、Y¹、Y³、X¹、及びX²は、式XIIIにおいて定義したとおりである。 In one embodiment, R ¹ is:

And
In the formula, R ² , R ³ , Y ¹ , Y ³ , X ¹ , and X ² are as defined in Formula XIII.

であり、
式中、R²、R³、Y¹、Y³、X¹、及びX²は、式XIIIにおいて定義したとおりである。 In one embodiment, R ¹ is:

And
In the formula, R ² , R ³ , Y ¹ , Y ³ , X ¹ , and X ² are as defined in Formula XIII.

であり、
式中、R²、R³、R⁶、Y、及びX¹は、式XIII、XX、XXI、又はXXIIにおいて定義したとおりである。 In one embodiment, R ¹ is:

And
Wherein R ² , R ³ , R ⁶ , Y, and X ¹ are as defined in formula XIII, XX, XXI, or XXII.

であり、
式中、R²、R³、R⁶、R⁷、X、及びBase*は、式XIII、XX、XXI、XXII、XL、XLI、又はXLIIにおいて定義したとおりである。 In one embodiment, R ¹ is:

And
In the formula, R ² , R ³ , R ⁶ , R ⁷ , X, and Base * are as defined in the formulas XIII, XX, XXI, XXII, XL, XLI, or XLII.

であり、
式中、R⁸は、アルキル、アルケニル、又はアルキニルであり；R⁷は、OR^7aであり；
R⁹は、OR^7aであり；
R^7aは、H、又は

であり；
R^mは、任意に天然又は非天然のアミノ酸の側鎖であり；かつ
R^pは、水素、ヒドロキシ、アルキル、又はアルコキシであり；かつ
Base*は、式XL、XLI、又はXLIIにおいて定義したとおりである。
一つの実施態様においてR⁸は、メチル、エチル、ビニル、又はエチニルであり；R⁷は、ヒドロキシ、又はフルオロであり；R⁹は、ヒドロキシであり、かつその他の変数は、本明細書に記述したとおりである。 In one embodiment, R ¹ is:

And
In which R ⁸ is alkyl, alkenyl, or alkynyl; R ⁷ is OR ^7a ;
R ⁹ is OR ^7a ;
R ^7a is H or

Is;
R ^m is optionally the side chain of a natural or non-natural amino acid; and
R ^p is hydrogen, hydroxy, alkyl, or alkoxy; and
Base * is as defined in Formula XL, XLI, or XLII.
In one embodiment, R ⁸ is methyl, ethyl, vinyl, or ethynyl; R ⁷ is hydroxy, or fluoro; R ⁹ is hydroxy, and other variables are described herein. Just as you did.

である。 In one embodiment, R ¹ is:

It is.

である。 In one embodiment, R ⁸ is methyl or ethyl. In one embodiment, R ^7a is H, or

It is.

、又はその医薬として許容し得る塩、溶媒和物、若しくは水和物である。 In one embodiment, the phosphoramidate compound provided herein is:

Or a pharmaceutically acceptable salt, solvate or hydrate thereof.

である。 In one embodiment, the phosphoramidate compound provided herein is:

It is.

である。 In one embodiment, the phosphoramidate compound provided herein is:

It is.

である。 In one embodiment, the phosphoramidate compound provided herein is:

It is.

である。 In one embodiment, the phosphoramidate compound provided herein is:

It is.

である。 In one embodiment, the phosphoramidate compound provided herein is:

It is.

である。 In one embodiment, the phosphoramidate compound provided herein is:

It is.

である。 In one embodiment, the phosphoramidate compound provided herein is:

It is.

である。 In one embodiment, the phosphoramidate compound provided herein is:

It is.

である。 In one embodiment, the phosphoramidate compound provided herein is:

It is.

である。 In one embodiment, the phosphoramidate compound provided herein is:

It is.

である。 In one embodiment, the phosphoramidate compound provided herein is:

It is.

である。 In one embodiment, the phosphoramidate compound provided herein is:

It is.

である。 In one embodiment, the phosphoramidate compound provided herein is:

It is.

である。 In one embodiment, the phosphoramidate compound provided herein is:

It is.

などのPMPA又はPMEAのホスホノアミダート形態である。 In one embodiment, the phosphonoamidate compound provided herein is:

The phosphonoamidate form of PMPA or PMEA.

(Optically active compound)
It will be appreciated that the compounds provided herein may have several chiral centers and exist in optically active and racemic forms and may be isolated. Some compounds will exhibit polymorphism. Any racemic, optically active, diastereoisomeric, polymorphic, or stereoisomeric form of the compounds provided herein having the useful properties described herein, or mixtures thereof are also included in the present invention. It is understood that it is within the range. Methods for preparing optically active forms are well known in the art (eg, by resolution of racemic forms by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chiral stationary phases. Depending on the chromatographic separation used).

  In particular, since the 1 'and 4' carbons of nucleosides are chiral, these non-hydrogen substituents (base and CHOR groups, respectively) can be cis (on the same side) or trans (opposite) with respect to the sugar ring system. Can be either side). Thus, the four optical isomers are represented by the following configuration (when the sugar residue is oriented in the horizontal plane so that the oxygen atom is on the back): cis (both groups “up”, naturally Corresponding to the configuration of β-D nucleosides present), cis (both groups are “bottom”, non-naturally occurring β-L configuration), trans (C2 ′ substituent is “top”, and C4 ′ Substituent is “bottom”) and trans (C2 ′ substituent is “bottom” and C4 ′ substituent is “top”). A “D-nucleoside” is a cis nucleoside in a naturally occurring configuration, and an “L-nucleoside” is a cis nucleoside in a non-naturally occurring configuration.

  Similarly, most amino acids are chiral (named as L or D, the L enantiomer is the naturally occurring configuration), and can exist as separate enantiomers.

Examples of methods for obtaining optical rotatory materials are known in the art and include at least the following.
i) (Physical separation of crystals)-A technique by which macroscopic crystals of individual enantiomers are separated manually. This technique can be used when there are separate enantiomeric crystals, ie the material is conglomerate and the crystals are visually different;
ii) (simultaneous crystallization)-a technique by crystallizing the individual enantiomers separately from the racemic solution, only possible if the latter is conglomerate in the solid state;
iii) (enzyme resolution)-a technique by partial or complete separation of racemates due to different rates of reaction of the enzyme to the enantiomer;
iv) (enzymatic asymmetric synthesis)-a synthetic technique by using an enzymatic reaction in at least one step of the synthesis to obtain an enantiomerically pure or concentrated synthetic precursor of the desired enantiomer;
v) (Chemical Asymmetric Synthesis) —Achiral precursors of the desired enantiomers under conditions that result in product asymmetry (ie, chirality) that can be achieved using chiral catalysts or chiral auxiliaries. Synthesis technology by synthesizing from
vi) (Diastereomeric separation)-A technique by reacting a racemate with an enantiomerically pure reagent (chiral auxiliary) to convert the individual enantiomers to diastereomers. The resulting diastereomers are then separated by chromatography, or crystallization, by their current more different structural differences, later removing the chiral auxiliary to give the desired enantiomer;
vii) (asymmetric transformations in the first and second order)-by equilibrating diastereomers from the racemate to give preference in the diastereomeric solution from the desired enantiomer, or from the desired enantiomer A technique that disrupts the equilibrium by preferential crystallization of the diastereomers, and consequently, in principle, converts all materials to crystalline diastereomers from the desired enantiomer. The desired enantiomer is then liberated from the diastereomer;
viii) (kinetic resolution)-This technique allows partial or complete resolution of racemates by unequal reaction rates of chiral, non-racemic reagents, or catalysts and enantiomers under kinetic conditions. (Or further resolution of a partially resolved compound) refers to achievement;
ix) (Enantiospecific synthesis from non-racemic precursors)-by obtaining the desired enantiomer from a non-chiral starting material and with minimal or minimal loss of stereochemical integrity over the course of the synthesis Is a synthesis technology;
x) (Chiral Liquid Chromatography)-a technique by separating racemic enantiomers in a liquid mobile phase by their different interactions with a stationary phase. The stationary phase can consist of chiral material, or the mobile phase can contain additional chiral material to cause different interactions;
xi) (chiral gas chromatography)-a technique by volatilizing the racemate and separating the enantiomers by their different interactions in the gas mobile phase using a column containing a fixed non-racemic chiral adsorbed phase;
xii) (extraction with chiral solvent) —a technique by separating enantiomers by preferential dissolution of the enantiomers in a particular chiral solvent;
xiii) (Transportation through a chiral membrane)-a technique by keeping the racemate in contact with a thin film barrier. The barrier typically separates the two miscible fluids, one containing the racemate, which causes preferential transport across the membrane barrier due to driving forces such as concentration or pressure differences. Separation occurs as a result of the non-racemic chiral nature of the membrane through which only one enantiomer of the racemate can pass.

  In some embodiments, provided are phosphonoamidates, or compositions of phosphoramidate compounds substantially free of the indicated enantiomer of the nucleoside. In preferred embodiments, in the methods and compounds of the invention, the compound is substantially free of enantiomers. In some embodiments, the composition comprises a compound that is at least 85%, 90%, 95%, 98%, 99% to 100% by weight of the compound, with the remainder being other chemical species, Or including an enantiomer.

(Preparation of compound)
The compounds provided herein can be prepared, isolated, or obtained by any method apparent to those of skill in the art. Exemplary preparation methods are detailed in the examples below.

R^y、R⁷、R⁸、R⁹、R¹⁰上の、又は塩基上の任意の反応性の官能基を、カップリング反応の間に保護してもよい。当業者に公知の種々のカップリング剤を使用することができる。反応に使用するための例示的なカップリング剤には、HOBt（N-ヒドロキシベンゾトリアゾール）、HBTU（2-(1H-ベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルアミニウムヘキサフルオロホスフェート）、DCC（N,N'-ジシクロヘキシルカルボジイミド）、BOP（ベンゾトリアゾール-1-イル-オキシ-トリス-(ジメチルアミノ)-ホスホニウムヘキサフルオロホフェート）、PyBOP（1H-ベンゾトリアゾール-1-イルオキシトリピロリジノホスホニウムヘキサフルオロホスフェート）、及び当業者に公知のその他を含むが、限定されない。 In certain embodiments, the compounds provided herein can be prepared by coupling an alcohol and an H-phosphonate monoester, as illustrated in the reaction scheme below:

^{R y, R 7, R 8} , R 9, on R ^10, or any reactive functional groups on the bases, may be protected during the coupling reaction. Various coupling agents known to those skilled in the art can be used. Exemplary coupling agents for use in the reaction include HOBt (N-hydroxybenzotriazole), HBTU (2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethylamino Nitrohexafluorophosphate), DCC (N, N'-dicyclohexylcarbodiimide), BOP (benzotriazol-1-yl-oxy-tris- (dimethylamino) -phosphonium hexafluorophosphate), PyBOP (1H-benzotriazole-1 -Yloxytripyrrolidinophosphonium hexafluorophosphate), and others known to those skilled in the art, but are not limited.

A general scheme for the synthesis of hydroxy tBuSATE N-benzyl phosphoramidate nucleoside derivatives represented by B is provided in Scheme B1-B3 below.

Where, in the case of a reactive amine, R = H, Tr, MMTr, or DMTr; R ¹ , R ² , R ⁴ , R ⁶ = H, alkyl, or halo, and R ³ / R ⁵ are both H Or isopropylidene.

Scheme B1: Synthesis of H-phosphonate monoester reagents

Scheme B2: Synthesis of protected nucleosides (R = DMTr and / or R ³ / R ⁵ = isopropylidene)

Scheme B3: Coupling of reagent 5 with (non) protected nucleoside, oxidative amination, and deprotection steps

  In addition, the coupling of certain nucleosides, and analogs thereof, and prodrugs thereof are described in US Patent Nos. 6,812,219; 7,105,493; 7,101,861; 6,914,054; 6,555,676; 7,202,224; 7,105,499; 6,777,395; 6,914,054; 2007087960; 2007060541; 2007060505; 2007060504; 2007060503; 2007060498; 2007042991; 2007042990; 2007042940; 2007042939, and 2007007037735; International Publication Numbers WO04 / 003000; WO04 / 022999; WO04 / 002422; WO01 / 90121, and WO01 / 92282 It can be prepared according to the method. Other patents / patent applications that disclose nucleoside analogs for treating hepatitis C virus that can be derivatized as described herein include: BioChem Pharma, Inc. (now Shire) Biochem, Inc.) PCT / CA00 / 01316 (WO01 / 32153; filed on November 3, 2000) and PCT / CA01 / 00197 (WO01 / 60315; filed on February 19, 2001); PCT / US02 / 01531 (WO02 / 057425; filed on January 18, 2002); PCT / US02 / 03086 (WO02 / 057287; filed on January 18, 2002); US 7,202,224 by Merck & Co., Inc. 7,125,855; 7,105,499, and 6,777,395; PCT / EP01 / 09633 (WO02 / 18404; published August 21, 2001); US2006 / 0040890 by Roche; 2005/0038240; 2004/0121980; 6,846,810; 6,784,166, and 6,660,721; PCT Publication numbers WO01 / 79246 (filed on April 13, 2001), WO02 / 32920 (filed on October 18, 2001), and WO02 / 48165; US2005 / 0009737 and US2005 / 0009737 by Pharmaset Ltd., and 7,094,770 And 6,927,291. The contents of these references are hereby incorporated by reference in their entirety.

(Assay method)
The compounds can be assayed for HBV activity according to any assay method known to those skilled in the art. The compounds can be assayed for HCV activity according to any assay method known to those of skill in the art.

  In addition, the compounds can be assayed for accumulation in the subject's hepatocytes according to any assay known to those of skill in the art. In certain embodiments, the compound can be administered to a subject, and the subject's hepatocytes can be assayed for the compound, or a derivative thereof, such as a nucleoside, nucleoside phosphate, or a nucleoside triphosphate derivative thereof. .

  In one embodiment, the phosphoramidate or phosphonoamidate nucleoside compound is administered to a cell, such as a hepatocyte, in vivo or in vitro, and the nucleoside triphosphate level delivered into the cell is measured, and the compound's Shows delivery and triphosphorylation in cells. The level of intracellular nucleoside triphosphate can be measured using analytical techniques known in the art. Methods for detecting ddATP are described herein below by way of illustration, but other nucleoside triphosphates can be readily detected using appropriate controls, calibration samples, and assay techniques. it can.

  In one embodiment, ddATP concentration is measured in a sample by comparing against a calibration standard made from a control sample. The ddATP concentration in the sample can be measured using analytical methods such as HPLC LC MS. In one embodiment, the test sample is compared to a calibration curve made with ddATP of known concentration, thereby obtaining the concentration of that sample.

  In one embodiment, the sample is manipulated to remove impurities such as salts (Na +, K +, etc.) prior to analysis. In one embodiment, the lower limit of quantification is 0.2 pmol / mL for hepatocyte cell extracts, especially when reduced salts are present.

  In one embodiment, the method can successfully measure triphosphate nucleotides formed at a level of 1 to 10,000 pmol per million cells, eg, in cultured hepatocytes and HepG2 cells.

(how to use)
Various therapeutic agents phosphoramidates and phosphonoamidate compounds can be formed using methods available in the art and those disclosed herein. Such compounds can be used in some embodiments to enhance delivery of drugs to the liver.

  In one embodiment, the compound includes S-acyl-2-thioethyl phosphoramidate, or S-acyl-2-thioethylphosphonoamidate, such as S-pivaloyl-2-thioethyl phosphoramidate, or Contains S-hydroxypivaloyl-2-thioethylphosphonoamidate derivatives. Therapeutic agents that can be derivatized into phosphoramidate or phosphonoamidate compound forms include attachment of phosphoramidate or phosphonoamidate moieties, including, but not limited to, nucleosides and nucleoside analogs, including acyclic nucleosides. Any antiviral agent that contains or is derivatized to contain a reactive group for.

  Conveniently, such phosphoramidate and phosphonoamidate compounds can conveniently enhance delivery to the liver. In some embodiments, the compound can enable delivery of the active 5′-monophosphate of the nucleoside to the liver, thereby enhancing the formation of the active triphosphorylated compound.

  In one embodiment, for the treatment and / or prevention of a host infected with flaviviridae comprising administration of an effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. A method is provided herein. In one embodiment, provided herein is a method for treating HCV infection in a subject. In certain embodiments, the method is effective for treating or preventing HCV infection in combination with a second agent effective for treating or preventing infection, in a subject in need thereof. Administering an amount of such a compound. The compound can be any compound as described herein, and the second agent can be any second agent described in the art or described herein. In certain embodiments, the compound is in the form of a pharmaceutical composition, or dosage form, as described in the section above.

  Flaviviridae that can be treated is generally discussed in Fields Virology, Editors: Fields, BN, Knipe, DM and Howley, PM, Lippincott-Raven Publishers, Philadelphia, PA, Chapter 31, 1996. ing. In certain embodiments of the invention, the Flaviviridae is HCV. In another embodiment of the invention, the Flaviviridae is a flavivirus or pestivirus. Specific flaviviruses include, but are not limited to: Absettarov, Alfuy, Apoi, Aroa, Bagaza, Banzi, Bouboui , Bussuquara, Cacipacore, Cray Island, Dakar bat, Dengue 1, Dengue 2, Dengue 3, Dengue 4 ), Edge Hill, Entebbe bat, Gadgets Gully, Hanzalova, Hypr, Ilheus, Israel turkey meningoencephalitis, Japan Encephalitis (Japanese encephalitis), Jugra, Jutiapa, Kadam, Karshi, Kedougou, Ko Kokobera, Koutango, Kumlinge, Kunjin, Kyasanur Forest disease, Langat, Jumping ill, Meaban, Modoc, Montana Montana myotis leukoencephalitis, Murray valley encephalitis, Naranjal, Negishi, Ntaya, Omsk hemorrhagic fever, Phnom-Penh bat, Powassan, Rio Bravo, Rocio, Royal Farm, Russian spring-summer encephalitis, Saboya, St. Louis encephalitis encephalitis, Sal Vieja San Perlita, San Perlita, Saumarez Reef, Sepik, Sokuluk, Spondweni, Stratford, Tembusu, Tyuleniy, Uganda S, Usutu, Wesselsbron, West Nile ), Yaounde, Yellow fever, and Zika.

  Pestiviruses that can be treated are commonly discussed in Fields Virology, Editors: Fields, BN, Knipe, DM and Howley, PM, Lippincott-Raven Publishers, Philadelphia, PA, Chapter 33, 1996. Yes. Specific pestiviruses include, but are not limited to: bovine viral diarrhea virus (“BVDV”), classic swine fever virus (“CSFV”, also called swine cholera virus), and border disease virus (“BDV”). ").

  In certain embodiments, hepatitis B comprising administering an effective amount of a compound as described herein, eg, formula I, IIa, or IIb, a pharmaceutically acceptable salt thereof, or a composition. Provided herein are methods for the treatment and / or prevention of infection. In another embodiment, conditions associated with hepatitis B infection, such as anti-HBV antibody positive and HBV-positive conditions, chronic liver inflammation caused by HBV, cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis, and fatigue Methods of treatment and / or prevention are provided herein. In certain embodiments, provided herein are prophylactic methods for preventing or delaying the progression of clinical disease in individuals who are anti-HBV antibodies or HBV-antigen positive or exposed to HBV. .

  In certain embodiments, the subject can be any subject infected with or at risk of infection with HCV and / or HBV. Infection, or risk of infection, can be determined according to any technique deemed appropriate by one of ordinary skill in the art. In one embodiment, the subject is a human infected with HCV and / or HBV.

In certain embodiments, the subject has not previously received therapy or prevention for HCV and / or HBV infection. In further embodiments, the subject has previously received therapy or prevention for HCV and / or HBV infection. For example, in certain embodiments, the subject has not responded to HCV and / or HBV therapy. For example, under current interferon therapy, up to 50% of HCV subjects do not respond to therapy. In certain embodiments, the subject can be a subject who has received therapy but continues to suffer from a viral infection, or one or more symptoms thereof. In certain embodiments, the subject can be a subject who has received therapy but has failed to achieve a sustained virological response. In certain embodiments, the subject received therapy for HCV and / or HBV infection, but failed to show a 2 log ₁₀ decrease in HCV RNA levels after, for example, 12 weeks of therapy. Subjects who did not show a 2 log ₁₀ or more reduction in serum HCV RNA after 12 weeks of therapy are considered to have a 97-100% probability of no response.

  In certain embodiments, the subject is a subject who has discontinued HCV and / or HBV therapy due to one or more adverse events associated with the therapy. In certain embodiments, the subject is a subject for whom no current therapy is indicated. For example, certain therapies for HCV are associated with neuropsychiatric events. Interferon (IFN) -α plus ribavirin is associated with a high proportion of depression. Depressive symptoms were associated with worse outcomes in a number of medical disorders. Life-threatening or fatal neuropsychiatric events, including suicide, suicidal ideation, and murderous idea formation, depression, drug addiction / overdose recurrence, and aggressive behavior may occur during HCV therapy Occurs in subjects with and without previous mental disorders. Interferon-induced depression is a limiting treatment for chronic hepatitis C, especially for subjects with mental disorders. Psychiatric side effects are common with interferon therapy and cause about 10% to 20% interruption of current therapy for HCV infection.

  Accordingly, methods are provided for treating or preventing HCV infection in subjects who are contraindicated for treatment with current HCV therapy due to the risk of neuropsychiatric events such as depression. In one embodiment, a method is provided for treating or preventing HCV infection in a subject who exhibits an interruption in treatment with current HCV therapy due to a neuropsychiatric event such as depression, or such risk. A neuropsychiatric event such as depression, or such a risk, provides a method for treating or preventing HCV infection in a subject exhibiting a reduced dose of current HCV therapy.

  Also, current therapies are contraindicated in subjects who are hypersensitive to interferon or ribavirin, or both, or any other component of a pharmaceutical for administration of interferon or ribavirin. Current therapies are not indicated in subjects who are dyslipidemic (eg, severe Mediterranean anemia, sickle cell anemia) and other subjects who are at risk from the hematologic side effects of current therapies. Common hematological side effects include myelosuppression, neutropenia, and thrombocytopenia. Furthermore, ribavirin is toxic to red blood cells and is associated with hemolysis. Thus, in one embodiment, subjects who are hypersensitive to interferon or ribavirin, or both, subjects who have dyslipidemia, such as severe Mediterranean anemia subjects, and sickle cell anemia subjects, and hematology of current therapies A method of treating or preventing HCV infection in other subjects at risk from potential side effects is provided.

  In certain embodiments, the subject has received HCV and / or HBV therapy and discontinued the therapy prior to administration of the methods provided herein. In further embodiments, the subject is receiving therapy and continues to receive the therapy along with administration of the methods provided herein. The method can be co-administered with other therapies for HBC and / or HCV according to the judgment of one of ordinary skill in the art. In certain embodiments, the methods or compositions provided herein can be co-administered with reduced doses of HBC and / or other therapies for HCV.

  In certain embodiments, a method of treating a subject that is refractory to treatment with interferon is provided. For example, in some embodiments, the subject is selected from the group consisting of interferon, interferon alpha, pegylated interferon alpha, interferon plus ribavirin, interferon alpha plus ribavirin, and pegylated interferon alpha plus ribavirin 1 The subject may have failed to respond to treatment with more than one drug. In some embodiments, the subject is one or more selected from the group consisting of interferon, interferon alpha, pegylated interferon alpha, interferon plus ribavirin, interferon alpha plus ribavirin, and pegylated interferon alpha plus ribavirin. Subjects who have not responded sufficiently to treatment with other drugs. A prodrug form of ribavirin such as taribavirin may also be used.

  In certain embodiments, the subject is co-infected or at risk for HIV and HCV. For example, in the United States, 30% of HIV subjects are co-infected with HCV, and evidence shows that people infected with HIV have a very rapid course of their hepatitis C infection. Maier and Wu, 2002, World J Gastroenterol 8: 577-57. The methods provided herein can be used to treat or prevent HCV infection in such subjects. It is believed that removal of HCV in these subjects will reduce mortality for end-stage liver disease. Indeed, the risk of progressive liver disease is higher in subjects with immunodeficiencies that define severe AIDS than in those who do not. See, for example, Lesens et al., 1999, J Infect Dis 179: 1254-1258. In one embodiment, the compounds provided herein have been shown to suppress HIV in HIV subjects. Accordingly, in certain embodiments, methods of treating or preventing HIV infection and HCV infection in a subject in need thereof are provided.

  In certain embodiments, the compound or composition is administered to the subject after liver transplantation. Hepatitis C is a leading cause of liver transplantation in the United States, and many subjects who undergo liver transplantation remain HCV positive after transplantation. In one embodiment, a method of treating with such a compound or composition provided herein for a recurrent HCV subject is provided. In certain embodiments, a method of treating a subject prior to, during, or after liver transplantation is provided to prevent recurrent HCV infection.

  In certain embodiments, provided herein. Chronic liver inflammation caused by hepatitis B infection and other related conditions, such as anti-HBV antibody positive and HBV-positive conditions, including administering an effective amount of a compound or composition provided herein Provided herein are methods for the treatment and / or prevention of cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis, and fatigue.

  In one embodiment, hepatitis B infection and other related conditions, such as anti-HBV antibody positive and HBV-positive conditions, comprising administering an effective amount of a compound or composition provided herein, Provided herein are methods for the treatment and / or prevention of chronic liver inflammation, cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis and fatigue caused by HBV.

(Second treatment)
In certain embodiments, the compounds and compositions provided herein are useful in methods of treating liver disorders and for treating disorders such as HCV and / or HBV infection in a subject in need thereof. Further administration of a second agent effective in The second agent can be any agent known to those of skill in the art to be effective for the treatment of the disorder, including those currently approved by the FDA.

  In certain embodiments, the compounds provided herein are administered in combination with one second agent. In a further embodiment, the second agent is administered in combination with two second agents. In still further embodiments, the second agent is administered in combination with two or more second agents.

  The term “in combination” as used herein includes the use of multiple therapies (eg, one or more prophylaxis and / or therapeutic agents). The use of the term “in combination” does not limit the order of therapies (eg, prophylactic and / or therapeutic agents) administered to a subject with a disorder. A first therapy (eg, a prophylactic or therapeutic agent such as a compound provided herein) is administered prior to administration of a second therapy (eg, a prophylactic or therapeutic agent) to a subject with a disorder ( For example, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before, simultaneously, or after (eg, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, followed by 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks).

  As used herein, the term “synergistic” refers to a compound provided herein and another that has been used or currently used to prevent, manage, or treat a disorder. In combination with a therapy (eg, prophylactic or therapeutic agent), including that this is more effective than the additive effects of therapy. Due to the synergistic effect of a combination of therapies (eg, prophylactic or therapeutic combinations), the use of one or more reduced dosages of the therapy for the subject with the disorder and / or less frequent administration of the therapy It becomes possible. The effectiveness of the therapy in preventing or treating disorders by utilizing lower dosages (eg, prophylactic or therapeutic agents) and / or being able to administer the therapy less frequently Without reducing the toxicity associated with administration of the therapy to a subject. In addition, synergistic effects can result in improved efficacy of drugs in preventing or treating disorders. Finally, the synergistic effect of a combination of therapies (eg, prophylactic or therapeutic combinations) avoids or reduces harmful or unwanted side effects associated with the use of the therapy alone. Also good.

The active compounds provided herein can be administered in combination or alternately with another therapeutic agent, particularly an anti-HCV agent, or a hepatitis B agent. In combination therapy, effective dosages of two or more drugs are administered together, whereas in alternating or sequential process therapy, effective dosages of each drug are administered sequentially or sequentially. The dosage given will depend on the absorption, inactivation, and excretion rates of the drug, as well as other factors known to those skilled in the art. It should also be noted that dosage values will vary depending on the severity of the condition being alleviated. For any particular subject, the specific dosing schedule and dosing schedule should be adjusted gradually according to the individual needs and the professional judgment of the person administering or supervising the administration of the composition. Will be further understood. In certain embodiments, anti-HCV (or anti-pestivirus, or anti-flavivirus) compounds that exhibit an EC ₅₀ of 10-15 μM, or preferably less than 1-5 μM, are desirable.

  It is recognized that drug-resistant mutants of flaviviruses, pestiviruses, or HCV can appear after long-term treatment with antiviral drugs. Drug resistance is most typically caused by mutations in the gene encoding the enzyme used for viral replication. Drug efficacy against viral infections is prolonged by administering the compound in combination or alternatively with a second and possibly third antiviral compound that induces a mutation different from that caused by the base drug , Increase, or recover. Alternatively, drug pharmacokinetics, biodistribution, or other parameters can be altered by such combination therapy or alternation therapy. In general, this is typically preferred over alternation therapy because combination therapy induces multiple simultaneous stresses on the virus.

  Any virus therapy described in the background of the invention can be used in combination or alternation with the compounds described herein. Non-limiting examples of second agents include the following:

  HCV protease inhibitors: Examples include Medivir HCV protease inhibitors (Medivir / Tobotec); ITMN-191 (InterMune), SCH 503034 (Schering), and VX950 (Vertes). Additional examples of protease inhibitors include: substrate-based NS3 protease inhibitors, including alpha ketoamide, and hydrazinourea (Attwood et al., Antiviral peptide derivatives, PCTWO 98/22496, 1998; Attwood et al. Literature, antiviral chemicals and chemotherapy 1999, 10, 259-273; Attwood et al., Preparation and use of amino acid derivatives as antiviral drugs, German Patent Publication DE 19914474; Tung et al., Serine protease In particular, inhibitors of hepatitis C virus NS3 protease, PCTWO98 / 17679), and inhibitors that terminate with electrophiles such as boronic acid or phosphonate (Llinas-Brunet et al., Hepatitis C inhibitor peptide analogs, PCTWO99 / 07734); RD3-4082, and RD3-4078 (the former is substituted on the amide with a 14 carbon chain, the latter processes the para-phenoxyphenyl group Non-substrate based NS3 protease inhibitors such as 2,4,6-trihydroxy-3-nitro-benzamide derivatives (Sudo K. et al., Biochemical and Biophysical Research Communications, 1997, 238, 643-647; Sudo K. et al. Antiviral Chemistry and Chemotherapy, 1998, 9, 186); and HCV protease inhibitor Sch 68631, phenanthrenequinone, (Chu M. et al., Tetrahedron Letters 37: 7229-7232, 1996).

  SCH 351633, isolated from the fungus Penicillium griseofulbum, has been identified as a protease inhibitor (Chu M. et al., Bioorganic and Medicinal Chemistry Letters 9: 1949-1952). Egrin c isolated from leech is a potent inhibitor of several serine proteases such as S. griseus protease A and B, α-chymotrypsin, chymase, and subtilis. Qasim M.A. et al., Biochemistry 36: 1598-1607, 1997.

  US patents that disclose protease inhibitors for the treatment of HCV include, for example: US Pat. No. 6,004,933 to Spruce et al., Which discloses a class of cysteine protease inhibitors for inhibiting HCV endopeptidase 2; C US Pat. No. 5,990,276 to Zhang et al. Discloses inhibitors of synthesis of hepatitis C virus NS3 protease; US Pat. No. 5,538,865 to Reyes et al .; WO02 / 008251 to Corvas International; and US 7,169,760 to Schering Corporation; US2005 / 176648 , WO02 / 08187, and WO02 / 008256. HCV inhibitor tripeptides are disclosed in US Pat. Nos. 6,534,523, 6,410,531, and 6,420,380 to Boehringer Ingelheim, and WO02 / 060926 to Bristol Myers Squibb. Diaryl peptides as NS3 serine protease inhibitors of HCV are disclosed in WO02 / 48172 to Schering Corporation and US 6,911,428. Imidazoleidinones as HCV NS3 serine protease inhibitors are disclosed in WO02 / 08198 and US6,838,475 to Schering Corporation and WO02 / 48157 and US6,727,366 to Bristol Myers Squibb. Also, WO 98/17679 and US 6,265,380 to Vertex Pharmaceuticals and WO 02/48116 and US 6,653,295 to Bristol Myers Squibb disclose HCV protease inhibitors. Further examples of HCV serine protease inhibitors are US 6,872,805 (Bristol-Myers Squibb); WO2006000085 (Boehringer Ingelheim); US7,208,600 (Vertex); US2006 / 0046956 (Schering-Plaugh); WO2007 / 001406 (Chiron); 2005/0153877; WO2006 / 119061 (Merck); WO00 / 09543 (Boehringer Ingelheim) US 6,323,180 (Boehringer Ingelheim), WO03 / 064456 (Boehringer Ingelheim), US6,642,204 (Boehringer Ingelheim), WO03 / 064416 (Boehringer Ingelheim), US7 , 091,184 (Boehringer Ingelheim) WO03 / 053349 (Bristol-Myers Squibb), US6,867,185, WO03 / 099316 (Bristol-Myers Squibb), US6,869,964, WO03 / 099274 (Bristol-Myers Squibb), US6,995,174, WO2004 / 032827 (Bristol-Myers Squibb), US7,041,698, WO2004 / 043339, and US6,878,722 (Bristol-Myers Squibb).

  NS3 / 4A fusion proteins, and thiazolidine derivatives that show related inhibition in reverse phase HPLC assays with NS5A / 5B substrates, particularly compounds RD-1-6250, RD4, which have a fused cinnamoyl moiety substituted with a long alkyl chain 6205, and RD4 6193 (Sudo K. et al., Antiviral Research, 1996, 32, 9-18);

  Kakiuchi N. et al., J. EBS Letters 421, 217-220; Thiazolidine identified in Takeshita N. et al., Analytical Biochemistry, 1997, 247, 242-246, and benzanilide;

  SCH 68631 (Chu M. et al., Tetrahedron Letters, SDS-PAGE isolated from fermentation culture broth of Streptomyces sp. And phenanthrenequinone with activity against proteases in autoradiographic assays. 1996, 37, 7229-7232), and SCH 3516331 (Chu M. et al., Bioorganic and Medicinal Chemistry Letters 9, 1949-1952), isolated from the fungus Penicillium griseofulbum that is active in scintillation proximity assays ;

  Helicase inhibitors (compounds, compositions and methods for the treatment of hepatitis C, US Pat. No. 5,633,358; Diana GD et al., Diana GD et al., Piperidine derivatives in the treatment of hepatitis C, pharmaceutical compositions thereof And their use, PCTWO 97/36554);

  Nucleotide polymerase inhibitors and gliotoxin (Ferrari R. et al., Journal of Virology, 1999, 73, 1649-1654) and natural product cerulenin (Lohmann V. et al., Virology, 1998, 249, 108-118) );

  Antiviral drugs based on short interfering RNA (siRNA) such as Sirna-034 and others described in International Publication Nos. WO / 03/070750 and WO2005 / 012525 and US Patent Publication No. US 2004/0209831 Antiviral drugs based on interfering RNA (iRNA).

  An antisense phosphorothioate oligodeoxynucleotide (S-ODN) complementary to a sequence stretch of the 5 'non-coding region (NCR) of the virus (Alt M. et al., Hepatology, 1995, 22, 707-717 ), Or nucleotides 326-348 containing the 3 'end of NCR, and nucleotides 371-388 located in the core coding region of HCV RNA (Alt M. et al., Archives of Virology, 1997, 142, 589-599; Galderisi U. et al., Journal of Cellular Physiology, 1999, 181, 251-257);

  Inhibitors of IRES-dependent translation (Ikeda N et al., Drug for prevention and treatment of hepatitis C, Japanese Patent Publication JP-08268890; Kai Y. et al., Prevention and treatment of viral diseases, Japanese Patent Publication JP-10101591);

  Nuclease resistant ribozymes (Maccjak, DJ et al., Hepatology 1999, 30, abstract 995) and ribozymes such as those disclosed in US Pat. No. 6,043,077 to Barbe et al. And US Pat. Nos. 5,869,253 and 5,610,054 to Draper As well as

  Nucleoside analogues have also been developed for the treatment of Flaviviridae infections.

  In certain embodiments, a compound provided herein is in combination with any of the compounds described by Idenix Pharmaceuticals International Publication Nos. WO01 / 90121, WO01 / 92282, WO2004 / 003000, WO2004 / 002422, and WO2004 / 002999. Can also be administered.

  Other patent applications that disclose the use of certain nucleoside analogs that can be used as second agents for treating hepatitis C virus include: by BioChem Pharma (now Shire Biochem) PCT / CAOO / 01316 filed (WO01 / 32153; filed on November 3, 2000) and PCT / CA01 / 00197 (WO01 / 60315; filed on February 19, 2001); by Merck & Co. PCT / US02 / 01531 (WO02 / 057425; filed on January 18, 2002); PCT / US02 / 03086 (WO02 / 057287; filed on January 18, 2002); US7,202,224; 7,125,855; 7,105,499 and 6,777,395 PCT / EP01 / 09633 by Roche (WO02 / 18404; published on August 21, 2001); US2006 / 0040890; 2005/0038240; 2004/0121980; 6,846,810; 6,784,166 and 6,660,721; PCT publication number by Pharmaset, Ltd. WO01 / 79246 (filed on April 13, 2001), WO02 / 32920 (filed on October 18, 2001), and WO02 / 48165; US2005 / 0009737; US2005 / 0009737; 7,094,770, and 6,927,291.

  Additional compounds that can be used as second agents for treating hepatitis C virus are disclosed in PCT Publication No. WO99 / 43691 to Emory University entitled “2′-Fluoronucleoside”. The use of certain 2′-fluoro nucleosides to treat HCV is disclosed.

  Various other compounds that can be used as the second agent include 1-amino-alkylcyclohexane (US Pat. No. 6,034,134 to Gold et al.), Alkyl lipids (US Pat. No. 5,922,757 to Chojkier et al.), Vitamin E , And other antioxidants (US Pat. No. 5,922,757 to Chojkier et al.), Squalene, amantadine, bile acid (US Pat. No. 5,846,964 to Ozeki et al.), N- (phosphonoacetyl) -1-aspartic acid (Diana et al. US Patent No. 5,830,905), benzenedicarboxamide (US Patent No. 5,633,388 to Diana et al.), Polyadenylic acid derivatives (US Patent No. 5,496,546 to Wang et al.), 2 ', 3'-dideoxyinosine (US Patent to Yarchoan et al.) 5,026,687), benzimidazole (US Pat. No. 5,891,874 to Colacino et al.), Plant extract (US Pat. No. 5,837,25 to Tsai et al.). No. 7, U.S. Pat. No. 5,725,859 to Omer et al., And U.S. Pat. No. 6,056,961) and piperidenes (U.S. Pat. No. 5,830,905 to Diana et al.).

(An exemplary second agent for the treatment of HCV)
In one embodiment, one or more compounds provided herein include Intron A® (interferon α-2b), and Pegasys® (peginterferon α-2a); Roferon A® Trademark) (recombinant interferon α-2a), Infergen® (consensus interferon; interferon alfacon-1), PEG-intron® (pegylated interferon α-2b), and Pegasys® ) (Pegylated interferon α-2a) or other anti-hepatitis C virus interferons can be administered in combination or alternately.

  In one embodiment, the anti-hepatitis C virus interferon is infergen, IL-29 (peginterferon lambda), R7025 (Maxy-α), belerofon, oral interferon α, BLX-883 (Locteron ), Omega interferon, multiferon, clagainter ferron, albuferon, or REBIF®.

  In one embodiment, one or more compounds provided herein is an inhibitor of anti-hepatitis C virus polymerase, such as ribavirin, viramidine, NM 283 (baropicitabine), PSI-6130, R1626, HCV-796, or R7128. It can be administered in combination with agents or alternately.

  In certain embodiments, one or more compounds provided herein include ribavarin, and Intron A® (interferon α-2b), and Pegasys® (peginterferon α-2a). ); Roferon A® (recombinant interferon α-2a), Infergen® (consensus interferon; interferon alfacon-1), PEG-Intron® (pegylated interferon α-2b) , And in combination with anti-hepatitis C virus interferons such as Pegasys® (pegylated interferon α-2a).

  In one embodiment, one or more compounds provided herein are combined with an anti-hepatitis C virus protease inhibitor such as ITMN-191, SCH 503034, VX950 (telaprevir), or Medivir HCV protease inhibitor. Or can be administered alternately.

  In one embodiment, one or more compounds provided herein are combined with an anti-hepatitis C virus vaccine such as TG4040, PeviPROTM, CGI-5005, HCV / MF59, GV1001, IC41, or INNO0101 (E1) Or can be administered alternately.

  In one embodiment, the one or more compounds provided herein include an anti-hepatitis C virus monoclonal antibody such as AB68 or XTL-6865 (formerly HepX-C); or cicavir It can be administered in combination or alternately with anti-hepatitis C virus polyclonal antibodies.

  In one embodiment, the one or more compounds provided herein is an anti-hepatitis C virus immunomodulator such as Zadaxin® (thymalfasin), NOV-205, or Oglufanide. And can be administered in combination or alternately.

  In one embodiment, one or more compounds provided herein are Nexavar, doxorubicin, PI-88, amantadine, JBK-122, VGX-410C, MX-3253 (Ceglosivir), Subus (BIVN-401 or virostat), PF-03491390 (formerly IDN-6556), G126270, UT-231B, DEBIO-025, EMZ702, ACH-0137171, MitoQ, ANA975, AVI- 4065, Bavituxinab (Tarvacin), Alinia (nitrazoxanide), or PYN 17 can be administered in combination or alternately.

(Exemplary second agent for treatment of HBV)
It is recognized that drug-resistant mutants of HBV can appear after long-term treatment with antiviral drugs. Drug resistance is caused by mutations in the gene used to encode the DNA polymerase in the case of the enzymes used in the viral life cycle, most typically HBV. Drug efficacy against HBV infection is prolonged by administering the compound in combination or alternatively with a second and possibly third antiviral compound that induces a mutation different from that caused by the base drug , Increase, or recover. Alternatively, drug pharmacokinetics, biodistribution, or other parameters can be altered by such combination therapy or alternation therapy. In general, this is typically preferred over alternation therapy because combination therapy induces multiple simultaneous stresses on the virus.

The anti-hepatitis B virus activity of the compounds provided herein can be enhanced by administering one or more of these additional agents in combination or alternately. Alternatively, for example, one or more compounds provided herein can be administered in combination or alternation with any other known anti-hepatitis B virus agent. Such drugs include anti-hepatitis B virus interferons such as Intron A® (interferon α-2b) and Pegasys® (peginterferon α-2a); Epivir-HBV (lamivudine), Hepsera (Hepsera) (adefovir dipivoxil), baraclude (entecavir), Tyzeka (telbivudine), emtricitabine (FTC), clevudine (L-FMAU) Polymerase inhibitors such as (Viread) (tenofovir), Valtorcitabine, Amdoxovir, ANA 380, Pradefovir (remofovir), and RCV (racivir); Hi-8 HBV, Vaccines such as HepaVaxx B and HBV core antigen vaccine; and HepX, SpecifEx-HepB, Dakishin (Zadaxin), EHT899, Bay 41-4109 (UT 231-B), HepeX-B, and NOV-205 other agents, such as, or 2.2.15 cells in 15 of any showing an EC ₅₀ of less than micromolar Other Or a prodrug or pharmaceutically acceptable salt thereof. Some other examples of anti-HBV agents are provided in US Publication No. 20050080034 and International Publication No. WO2004 / 096286, which are incorporated by reference in their entirety.

  In one embodiment, one or more compounds provided herein are interferon alpha-2b, pegylated interferon alpha-2a, lamivudine, hepsera, baraclude, terbivudine, emtricitabine, clevudine, tenofovir, Administer in combination or alternately with anti-hepatitis B virus agents such as valtorcitabine, amdoxovir, ANA 380, remofovir, racivir, alinia, Hi-8 HBV, and HepaVaxx B be able to.

  In another embodiment, the compounds provided herein include proteins, peptides, oligos, including but not limited to antisense oligonucleotides to genes that express or regulate interferon, interleukin, or hepatitis B replication. It is administered in combination with, or alternately with, immune replicators of viral replication, including biological materials such as nucleotides or gamma globulin, or other pharmaceutically active modifiers.

  Any alternate method of providing treatment to the patient can be used. Non-limiting examples of alternating patterns include administration of an effective amount of one drug for 1-6 weeks followed by administration of an effective amount of a second anti-HBV drug for 1-6 weeks. The alternating schedule can include periods of no treatment. Combination therapy generally involves the co-administration of an effective ratio of dosages of two or more anti-HBV drugs.

  In view of the fact that HBV is often found in patients who are anti-HIV antibodies or HIV-antigen positive or exposed to HIV, or active anti-HBV compounds disclosed herein, or These derivatives, or prodrugs, can be administered in an appropriate environment in combination with or alternately with anti-HIV drug therapy.

  Also, the compounds provided herein can be administered in combination with antibiotics, other antiviral compounds, antifungal agents, or other pharmaceutical agents that are administered for the treatment of secondary infections.

(Pharmaceutical composition and administration method)
The various therapeutic agents phosphoramidates and phosphonoamidate compounds can be formulated into pharmaceutical compositions using methods available in the art and those disclosed herein. Such compounds can be used in some embodiments to enhance delivery of drugs to the liver. In one embodiment, the compound includes S-acyl-2-thioethyl phosphoramidate, or S-acyl-2-thioethyl phosphonoamidate, such as S-pivaloyl-2-thioethyl phosphoramidate, or Contains S-hydroxypivaloyl-2-thioethylphosphonoamidate derivatives. Therapeutic agents that can be derivatized to phosphoramidate or phosphonoamidate compound forms include attachment of phosphoramidate or phosphonoamidate moieties including, but not limited to, nucleosides and nucleoside analogs, including acyclic nucleosides. Any antiviral agent that contains or is derivatized to contain a reactive group for. Any of the phosphoramidate or phosphonoamidate compounds disclosed herein can be provided in a suitable pharmaceutical composition and can be administered by a suitable route of administration.

  The methods provided herein comprise a pharmaceutical composition comprising at least one compound as described herein comprising a compound of general formula I, IIa, or IIb, when appropriate, in a salt form, Or administration using in the form of one or more compatible and pharmaceutically acceptable carriers, such as diluents or adjuvants, or in combination with another anti-HCV or anti-HBV agent.

  In certain embodiments, the second agent can be formulated or packed with a compound provided herein. Of course, the second drug may be formulated with a compound provided herein, as such co-formulation should not interfere with either the activity of the drug or the method of administration, according to the judgment of one of ordinary skill in the art. Will only be done. In certain embodiments, the compound provided herein and the second agent are formulated separately. These can be packaged together or packaged separately for the convenience of those skilled in the art.

  In medical practice, the active agents provided herein may be administered by any conventional route, particularly orally, parenterally, rectally, or by inhalation (eg, in the form of an aerosol). Good. In certain embodiments, the compounds provided herein are administered orally.

  As solid compositions for oral administration, tablets, pills, hard gelatin capsules, powders or granules may be used. In these compositions, the active product is mixed with one or more inert diluents or adjuvants such as sucrose, lactose or starch.

  These compositions can include substances other than diluents, for example lubricants such as magnesium stearate, or coatings intended for sustained release.

  As liquid compositions for oral administration, pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water or liquid paraffin may be used. These compositions can also include substances other than diluents, such as wet products, sweet products, or flavor products.

  The composition for parenteral administration can be an emulsion or a sterile solution. As solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, or injectable organic esters such as ethyl oleate may be used. These compositions may also contain adjuvants, especially wetting agents, tonicity agents, emulsifiers, dispersants, and stabilizers. Sterilization can be performed in several ways, for example using a bacterial filter, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions that can be dissolved at the time of use in sterile water or any other sterile medium for injection.

  Compositions for rectal administration are suppositories or rectal capsules containing, in addition to the active ingredient, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

  The composition can also be an aerosol. For use in the form of a liquid aerosol, the composition may be a stable sterile solution that is dissolved at the time of use in non-pyrogenic sterile water, saline, or any other pharmaceutically acceptable medium, or a solid It can be a composition. For use in the form of a dry aerosol intended to be directly inhaled, the active ingredient is finely divided and combined with a water-soluble solid diluent or medium, such as dextran, mannitol, or lactose .

  In one embodiment, the compositions provided herein are pharmaceutical compositions or single unit dosage forms. The pharmaceutical compositions and single unit dosage forms provided herein include one or more prophylactic or therapeutic agents (eg, compounds provided herein, or other prophylactic or therapeutic agents). ) In a prophylactically or therapeutically effective amount and typically one or more pharmaceutically acceptable carriers or excipients. In certain embodiments, and in this context, the term “pharmaceutically acceptable” has been approved by the federal or state government regulatory agencies, or in the United States Pharmacopeia, or animals, and in more detail. Means listed in other commonly recognized pharmacopoeias for use in humans. The term “carrier” includes diluents, adjuvants (eg, Freund's adjuvant (complete and incomplete)), excipients, or vehicle in which the treatment is administered. Such pharmaceutical carriers can be sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water can be used as a carrier when the pharmaceutical composition is administered intravenously. Saline solutions and dextrose and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. Examples of suitable drug carriers are described in “Remington's Pharmaceutical Science” by E.W Martin.

  Typical pharmaceutical compositions and dosage forms contain one or more excipients. Suitable excipients are well known to those skilled in pharmacy and non-limiting examples of suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel , Sodium stearate, glycerol monostearate, talc, sodium chloride, dry skim milk, glycerol, propylene, glycol, water, ethanol, etc. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form includes the manner in which the dosage form will be administered to the subject, and the specific active ingredient in the dosage form, It depends on various factors well known in the art without limitation. The composition or single unit dosage form can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents as required.

  Lactose-free compositions provided herein include excipients that are well known in the art and are listed, for example, in the United States Pharmacopeia (USP) SP (XXI) / NF (XVI) Can do. In general, a lactose-free composition includes a pharmaceutically compatible and pharmaceutically acceptable amount of the active ingredient, a binder / filler, and a lubricant. Exemplary lactose-free dosage forms include the active ingredient, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

  Since water can facilitate the degradation of some compounds, pharmaceutical compositions containing the active ingredients and dosage form anhydrides are further included herein. For example, the addition of water (eg, 5%) is widely accepted in pharmaceutical technology as a means of simulating long-term storage to determine characteristics such as shelf life over a period of time or formulation stability. Yes. See, for example, Jens T. Carstensen, Drug Stability: Principles and Practice, 2nd edition, Marcel Dekker, NY, NY, 1995, pp. 379 80. In effect, water and heat promote the decomposition of some compounds. Thus, the effect of water on the formulation can be very significant because moisture and / or humidity generally occurs during preparation, handling, packaging, storage, shipment, and use of the formulation.

  Pharmaceutical compositions and dosage forms of the anhydrides provided herein can be prepared using an anhydride containing ingredients and low moisture or at low humidity or low moisture conditions. A pharmaceutical composition comprising lactose and an active ingredient comprising at least one primary or secondary amine, and a dosage form is substantially free of moisture and / or humidity during preparation, packaging and / or storage. If general contact is expected, it can be an anhydride.

  The anhydride of the pharmaceutical composition should be prepared and stored such that the nature of the anhydride is maintained. Thus, the anhydrides of the composition can be packed using materials known to prevent exposure to water, and thus can be included in a suitable formulary kit. Examples of suitable packaging include, but are not limited to, sealed foils, plastics, unit dose containers (eg, vials), blister packs, and strip packs.

  Further provided are pharmaceutical compositions and dosage forms comprising one or more compounds that reduce the rate at which the active ingredient will degrade. Such compounds are referred to herein as “stabilizers” and include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

  Pharmaceutical compositions and single unit dosage forms can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained release formulations, and the like. Oral formulations can include standard carriers such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and other pharmaceutical grades. Such compositions, and dosage forms, in certain embodiments, are prophylactic or prophylactic agents in purified form, with a suitable amount of carrier to provide a form for proper administration to a subject. Or a therapeutically effective amount. The formulation should suit the mode of administration. In certain embodiments, the pharmaceutical composition or single unit dosage form is sterile and in a form suitable for administration to a subject, eg, an animal subject such as a mammalian subject, eg, a human subject.

  A pharmaceutical composition is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, such as intravenous, intradermal, subcutaneous, intramuscular, subcutaneous, oral, buccal, sublingual, inhalation, intranasal, transdermal, topical, transmucosal, intratumoral, Including, but not limited to, bursa and rectal administration. In a specific embodiment, the composition is formulated according to routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration to humans. In certain embodiments, the pharmaceutical composition is formulated according to routine procedures for subcutaneous administration to humans. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing agent and a local anesthetic such as lignocaine that relieves pain at the site of injection.

  Examples of dosage forms include, but are not limited to: tablets; caplets; capsules such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; Powders; bandages; creams; plasters; solutions; patches; aerosols (eg, nasal sprays or inhalers); gels; suspensions (eg, aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or oils) Liquid dosage forms suitable for oral or mucosal administration to subjects, including water-in-water emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to subjects; and for parenteral administration to subjects A sterile solid (eg, a crystalline solid or an amorphous solid) that can be reconstituted to provide a liquid dosage form suitable for.

  The types of compositions, shapes, and dosage forms provided herein will typically vary depending on their use. For example, a dosage form used for initial treatment of a viral infection may contain a greater amount of one or more active ingredients it contains than a dosage form used for maintenance therapy of the same infection. Similarly, a parenteral dosage form may contain a smaller amount of one or more active ingredients it contains than an oral dosage form used to treat the same disease or disorder. These and other ways in which specific dosage forms encompassed herein will vary from one another will be readily apparent to those skilled in the art. See, for example, “Remington's Pharmaceutical Science”, 20th Edition, Mack Publishing, Easton PA (2000).

  In general, the components of the composition are contained in sealed containers, such as ampoules or sachets indicating the amount of active agent, for example as a dry lyophilized powder, or a water-free concentrate, either separately or in unit dosage form. Supplied either mixed. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.

  Typical dosage forms are in the range of about 0.1 mg to about 1000 mg per day, given as a once daily dose in the morning or as a divided dose taken with food throughout the day. It includes a compound provided herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof. Certain dosage forms contain about 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 100, 200, 250, 500, or 1000 mg of active compound. Can have.

(Oral dosage form)
Pharmaceutical compositions suitable for oral administration exist as separate dosage forms such as, but not limited to, tablets (eg, chewable tablets), caplets, capsules, and liquids (eg, flavored syrup). be able to. Such dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, “Remington's Pharmaceutical Science”, 20th Edition, Mack Publishing, Easton PA (2000).

  In certain embodiments, the oral dosage form is a solid and is prepared under anhydrous conditions with an anhydride component as described in detail in the section above. However, the range of compositions provided herein extends beyond anhydrous, solid oral dosage forms. Accordingly, further forms are described herein.

  A typical oral dosage form is prepared by combining the active ingredients in a homogeneous mixture with at least one excipient according to conventional pharmaceutical formulation techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration. For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, fragrances, preservatives, and coloring agents. Examples of excipients suitable for use in solid oral dosage forms (eg, powders, tablets, capsules, and caplets) include starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binding Including, but not limited to, agents and disintegrants.

  Because of their ease of administration, tablets and capsules are the most advantageous oral dosage unit form, in which case solid excipients are used. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such dosage forms can be prepared by any method of dispensing. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately mixing the active ingredient with liquid carriers, finely divided solid carriers, or both, and then if necessary shaping the product into the desired appearance. Is done.

  For example, a tablet can be prepared by compression or molding. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free flowing form, such as a powder or granules, optionally mixed with an excipient. A pill tablet may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

  Examples of excipients that can be used in oral dosage forms include, but are not limited to, binders, fillers, disintegrants, and lubricants. Suitable binders and dosage forms for use in pharmaceutical compositions include natural and synthetic gums such as corn starch, potato starch, or other starches, gelatin acacia, sodium alginate, alginic acid, other alginates, tragacanth Powder, guar gum, cellulose, and derivatives thereof (eg, ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methylcellulose (eg, numbers 2208, 2906, 2910), microcrystalline cellulose, as well as mixtures thereof.

  Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include talc, calcium carbonate (eg, granules or powder), microcrystalline cellulose, powdered cellulose, dextrates (Dextrates), kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof, but are not limited. The binder or filler in the pharmaceutical composition is typically present in about 50 to about 99 parts by weight of the pharmaceutical composition or dosage form.

  Suitable forms of microcrystalline cellulose include materials sold as AVICELPH 101, AVICELPH 103, AVICELRC 581, AVICELPH 105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof Including, but not limited to. A specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC 581. Suitable anhydrous or low moisture excipients or additives include AVICEL PH 103 ™ = and Starch 1500 LM.

  Disintegrants are used in the compositions to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate upon storage, while those that contain almost nothing may not disintegrate at the desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredient should be used to form a solid oral dosage form. The amount of disintegrant used will vary based on the type of formulation and is readily identifiable to those skilled in the art. A typical pharmaceutical composition comprises about 0.5 to about 15 parts by weight of a disintegrant, specifically about 1 to about 5 parts by weight of a disintegrant.

  Disintegrants that can be used in pharmaceutical compositions and dosage forms include agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato Or tapioca starch, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.

  Lubricants that can be used in pharmaceutical compositions and dosage forms include calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, Includes talc, hydrogenated vegetable oils (eg, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, and mixtures thereof However, it is not limited. Further lubricants include, for example, syloid silica gel (prepared by AEROSIL 200, WR Grace Co. of Baltimore, MD), coagulated aerosol of synthetic silica (sold by Degussa Co. of Piano, TX), CAB O SIL (pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA), and mixtures thereof. If used at all, lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.

(Slow release dosage form)
Active ingredients such as the compounds provided herein can be administered by sustained release means or by delivery devices that are well known to those of skill in the art. Examples include U.S. Patent Numbers: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,548; 6,589,548; Using such dosage forms, for example, hydropropyl methylcellulose, other polymer matrices, gels, osmotic membranes, osmotic systems, multilayer coatings, microparticles, to provide the desired release profile at various ratios, Slow release, or sustained release, of one or more active ingredients can be provided using liposomes, microparticles, or combinations thereof. Suitable sustained release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients provided herein. Thus, single unit dosage forms suitable for oral administration such as tablets, capsules, gelcaps, and caplets adapted for sustained release are encompassed herein.

  All sustained release pharmaceuticals have a common goal of improving drug therapy over that achieved by these uncontrolled counterparts. Ideally, the use of an optimally designed sustained release formulation in medical treatment is characterized by the smallest drug substance used to cure or control the condition in a minimal amount of time. Advantages of sustained release formulations include extended drug activity, reduced dosage frequency, and increased subject compliance. In addition, sustained release formulations can be used to affect other characteristics such as the onset time of action, or the blood level of the drug, thus affecting the occurrence of side effects (eg, adverse effects). be able to.

  Most sustained release formulations initially release the amount of drug (active ingredient) that rapidly produces the desired therapeutic effect and the drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. It is designed to release other amounts of in stages and continuously. In order to maintain this constant level of drug in the body, the drug must be metabolized and released from the dosage form at a rate that will compensate for the amount of drug excreted from the body. Sustained release of the active ingredient can be stimulated by a variety of conditions including but not limited to pH, temperature, enzymes, water, or other physiological conditions or compounds.

  In certain embodiments, the drug may be administered using intravenous infusion, implantable osmotic pumps, transdermal patches, liposomes, or other modes of administration. In one embodiment, a pump may be used (Sefton, CRC Crit. Ref. Biomed Eng. 14: 201 (1987); Buchwald et al., Surgery 88: 507 (1980); Saudek et al. N. Engl. J. Med. 321: 574 (1989)). In another embodiment, polymeric materials can be used. In yet another embodiment, the sustained release system can be placed at an appropriate site within the subject as determined by one skilled in the art, i.e., this only requires a portion of the systemic dose (e.g., Goodson). , Medical Applications of Controlled Release, vol. 2, pp. 115-138 (1984)). Other sustained release systems are discussed in a review by Langer (Science 249: 1527-1533 (1990)). The active ingredient is a solid internal matrix that is insoluble in body fluids such as polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, poly Hydrophilic polymers such as isobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, acrylic and methacrylic ester hydrogel, collagen, outer polymer membrane, For example, polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, neoprene rubber, Crosslinked polyvinyl alcohol and crosslinked partially hydrolyzed polyvinyl acetate surrounded by chlorinated polyethylene, polyvinyl chloride, vinyl chloride copolymer with vinyl acetate, vinylidene chloride, ethylene and propylene, It can be dispersed in noma polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer. The active ingredient then diffuses through the outer polymer membrane in a process that controls the release rate. The proportion of active ingredient in such parenteral compositions is highly dependent on the specific nature thereof, as well as the requirements of the subject.

(Parenteral dosage form)
In one embodiment, a parenteral dosage form is provided. Parenteral dosage forms can be administered to a subject by a variety of routes including, but not limited to, subcutaneous, intravenous (including bolus administration), intramuscular, and intraarterial. Since these administrations typically bypass the subject's natural defenses against contaminants, parenteral dosage forms are typically sterile or can be sterilized prior to administration to the subject. . Examples of parenteral dosage forms include solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable medium for injection, suspensions ready for injection, and Including but not limited to emulsions.

  Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art. Examples include, but are not limited to: distilled water USP for injection; aqueous media such as but not limited to sodium chloride injection, Ringer injection, dextrose injection, dextrose and sodium chloride injection, and lactated Ringer injection; Water miscible media such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-limiting such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate Aqueous medium.

  In addition, compounds that increase the solubility of one or more of the active ingredients disclosed herein can be incorporated into parenteral dosage forms.

(Transdermal, topical, and mucosal dosage forms)
Transdermal, topical, and mucosal dosage forms are also provided. Transdermal, topical, and mucosal dosage forms include, but are not limited to, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to those skilled in the art. Not. For example, “Remington's Pharmaceutical Science”, 16th, 18th and 20th editions, Mack Publishing, Easton PA (1980, 1990 &2000); and introduction to pharmaceutical dosage forms (Introduction to Pharmaceutical Dosage Forms), 4th edition, Lea, and Febiger, Philadelphia (1985). A dosage form suitable for treating mucosal tissue in the oral cavity can be formulated as a mouthwash or as an oral gel. Additional transdermal dosage forms include “reservoir-type” or “matrix-type” patches, which are applied to the skin for a specific period of time to allow permeation of the desired amount of active ingredient and worn. can do.

  Suitable excipients (eg, carriers and diluents), and other materials that can be used to provide transdermal, topical, and mucosal dosage forms encompassed herein are described in the pharmaceutical industry. Is well known to those of ordinary skill in the art and depends on the particular pharmaceutical composition or the particular tissue to which the dosage form will be applied. With this fact in mind, typical excipients include water, acetone, ethanol, ethylene to form non-toxic and pharmaceutically acceptable lotions, tinctures, creams, emulsions, gels, or ointments. Including but not limited to glycol, propylene glycol, butane 1,3 diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof. In addition, a moisturizer or wetting agent can be added to the pharmaceutical composition and dosage form as necessary. Examples of such additional components are well known in the art. See, for example, “Remington's Pharmaceutical Science”, 16th, 18th and 20th editions, Mack Publishing, Easton PA (1980, 1990 & 2000).

  Depending on the specific tissue being treated, additional components may be used prior to, in combination with, or after treatment with the provided active ingredient. For example, penetration enhancers can be used to assist in delivering the active ingredients to the tissue. Suitable permeation enhancers include, but are not limited to: acetone; various alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethylformamide; polyethylene glycol; Various water-soluble or water-insoluble sugar esters such as Kollidon grade (Povidone, Polyvidone); Urea; and Tween 80 (Polysorbate 80) and Span 60 (Sorbitan monostearate).

  In addition, the pH of the pharmaceutical composition or dosage form, or the pH of the tissue to which the pharmaceutical composition or dosage form is applied, may be adjusted to improve delivery of one or more active ingredients. Similarly, the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery. In addition, compounds such as stearates can be added to pharmaceutical compositions or dosage forms to conveniently change the hydrophilicity or lipophilicity of one or more active ingredients to improve delivery. In this regard, stearate can serve as a lipid vehicle for the formulation, as an emulsifier or surfactant, and as a delivery enhancer or permeation enhancer. Different salts, hydrates or solvates of the active ingredients can be used to further adjust the properties of the resulting composition.

(Dosage and unit dosage form)
In human therapy, a physician determines the dose that he considers optimal according to prophylactic or therapeutic treatment and according to age, weight, stage of infection, and other factors specific to the subject being treated. Will do. In certain embodiments, the dose is about 1 to about 1000 mg per day for adults, or about 5 to about 250 mg per day for adults, or about 10 to 50 mg per day. In certain embodiments, the dose is about 5 to about 400 mg per day for adults, or 25 to 200 mg per day. In certain embodiments, a dose rate of about 50 to about 500 mg per day is envisioned.

  In a further aspect, treating a subject in need thereof with an HCV and / or HBV infection in a subject by administering an effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or Methods are provided for prevention. The amount of the compound or composition that will be effective in preventing or treating the disorder, or one or more symptoms thereof, will vary depending on the nature and severity of the disease or condition and the route to which the active ingredient is administered. Will. Also, the frequency and dosage will depend on the specific therapy being administered (eg, therapeutic or prophylactic agent), the severity of the disorder, disease or condition, the route of administration, and the age, body, weight, Depending on the response and past medical history, each subject will vary according to specific factors. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

  In certain embodiments, exemplary doses of the composition include milligrams of active compound per kilogram of subject or sample weight, or microgram quantities (eg, about 10 micrograms per kilogram to about 50 per kilogram Milligrams, about 100 micrograms per kilogram to about 25 milligrams per kilogram, or about 100 micrograms per kilogram to about 10 milligrams per kilogram). For the compositions provided herein, in certain embodiments, the dosage administered to a subject is 0.140 mg / kg to 3 mg / kg of the subject's body weight, based on the weight of the active compound. In certain embodiments, the dosage administered to a subject is between 0.20 mg / kg to 2.00 mg / kg of the subject's body weight, or between 0.30 mg / kg to 1.50 mg / kg.

  In certain embodiments, the recommended daily dose range of the compositions provided herein for the conditions described herein is in the range of about 0.1 mg to about 1000 mg per day, and a single It is given as a once-daily dose or as divided doses throughout the day. In one embodiment, the daily dose is administered twice daily in equally divided doses. In certain embodiments, the daily dose range is between about 10 mg to about 200 mg per day, in other embodiments between about 10 mg to about 150 mg per day, and in further embodiments about 25 mg per day. Should be between ~ 100 mg. In some cases, it may be necessary to use dosages of the active ingredient outside the ranges disclosed herein, as will be apparent to those skilled in the art. Furthermore, it should be noted that the health care professional or treating physician will know how and when to interrupt, adjust or terminate therapy in combination with the subject's response.

  As will be readily appreciated by those skilled in the art, different therapeutically effective amounts will apply to different diseases and conditions. Similarly, sufficient to prevent, manage, treat or ameliorate such disorders, but not enough or reduced to cause the adverse effects associated with the compositions provided herein. Sufficient amounts to be included are included in the dosage and dose frequency schedules described above. Furthermore, when multiple agents of the compositions provided herein are administered to a subject, not all of the dosages need be the same. For example, the dosage administered to a subject may be increased to improve the prophylactic or therapeutic effect of the composition, or decreased to reduce one or more side effects experienced by a particular subject. May be.

  In certain embodiments, provided herein, based on the weight of an active compound administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof, in a subject. The dosage of the composition is 0.1 mg / kg, 1 mg / kg 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 10 mg / kg, or 15 mg / kg or more of the subject's body weight . In another embodiment, a dosage of a composition provided herein administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof, in a subject, or The composition is 0.1 mg to 200 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 7.5 mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 mg to 7.5 mg, 0.25 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, A unit dosage of 1 mg to 10 mg, 1 mg to 7.5 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg.

  In certain embodiments, treatment or prevention can be initiated with one or more loading doses of a compound or composition provided herein followed by one or more maintenance doses. In such embodiments, the loading dose can be, for example, from about 60 to about 400 mg per day, or from about 100 to about 200 mg per day, from 1 day to 5 weeks. The loading dose can be followed by one or more maintenance doses. In certain embodiments, each maintenance dose is independently about 10 mg to about 200 mg per day, between about 25 mg to about 150 mg per day, or between about 25 to about 80 mg per day. The maintenance dose can be administered daily and can be administered as a single dose or as divided doses.

  In certain embodiments, a dose of a compound or composition provided herein can be administered to achieve a steady state concentration of the active ingredient in the blood or serum of the subject. The steady state concentration can be determined by measurements according to techniques available to those skilled in the art or can be based on physical characteristics such as the height, weight, and age of the subject. In certain embodiments, a sufficient amount of a compound or composition provided herein is about 300 to about 4000 ng / mL, about 400 to about 1600 ng / mL, or about 600 to about 1200 ng / mL of a subject. Administered to achieve steady state concentrations in blood or serum. In some embodiments, the loading dose is administered to achieve a steady state blood or serum concentration of about 1200 to about 8000 ng / mL, or about 2000 to about 4000 ng / mL for 1 to 5 days. be able to. In certain embodiments, the maintenance dose is such as to achieve a steady state concentration in the blood or serum of the subject from about 300 to about 4000 ng / mL, from about 400 to about 1600 ng / mL, or from about 600 to about 1200 ng / mL. Can be administered.

  In certain embodiments, administration of the same composition may be repeated and administration is at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, February, 75 days May be separated until March or June. In other embodiments, administration of the same prophylactic or therapeutic agent may be repeated, and administration is at least 1, 2, 3, 5, 10, 15, 30, 45, May be separated until February, 75th, March or June.

  In certain embodiments, provided herein are unit dosages comprising a compound, or a pharmaceutically acceptable salt, in a form suitable for administration. Such forms are described in detail above. In certain embodiments, the unit dosage comprises 1-1000 mg, 5-250 mg, or 10-50 mg of active ingredient. In particular embodiments, the unit dosage comprises about 1, 5, 10, 25, 50, 100, 125, 250, 500, or 1000 mg of active ingredient. Such unit dosages can be prepared according to techniques well known to those skilled in the art.

  The dosage of the second agent is used in the combination therapy provided herein. In certain embodiments, dosages used to prevent or treat HCV and / or HBV infection or lower than those currently used are used in the combination therapy provided herein. Is done. The recommended dosage of the second agent can be obtained from the knowledge of those skilled in the art. For these second agents approved for clinical use, for example, recommended dosages are described in Hardman et al., 1996, Gilman & Goodman therapeutics, which is incorporated herein by reference in its entirety. Goodman & Gilman's The Pharmacological Basis Of Basis Of Therapeutics, 9th edition, Mc-Graw-Hill, New York; Hysician's Desk Reference (PDR), 57th edition, 2003, Medical Economics Co., Inc., Montvale, NJ.

  In various embodiments, the therapy (eg, a compound provided herein and a second agent) is administered at intervals of less than 5 minutes, at intervals of less than 30 minutes, at intervals of 1 hour, at intervals of about 1 hour. About 1 hour to about 2 hours, about 2 hours to about 3 hours, about 3 hours to about 4 hours, about 4 hours to about 5 hours, about 5 hours to about 6 hours About 6 hours to about 7 hours, about 7 hours to about 8 hours, about 8 hours to about 9 hours, about 9 hours to about 10 hours, about 10 hours to about 11 hours About 11 hours to about 12 hours, about 12 hours to 18 hours, 18 hours to 24 hours, 24 hours to 36 hours, 36 hours to 48 hours, 48 hours to 52 hours At intervals of 52-60 hours, at intervals of 60-72 hours, at intervals of 72-84 hours, at intervals of 84-96 hours, or at intervals of 96-120 hours. In various embodiments, the therapy is administered within a 24-hour interval, or within a 48-hour interval. In certain embodiments, more than one therapy is administered within the same patient visit. In other embodiments, the compound provided herein and the second agent are administered simultaneously.

  In other embodiments, the compound provided herein and the second agent are about 2-4 days apart, about 4-6 days apart, about 1 week apart, about 1-2 weeks apart. Or at intervals of 2 weeks or more.

  In certain embodiments, administration of the same agent may be repeated and administration is at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, February, 75 days May be separated until March or June. In other embodiments, administration of the same agent may be repeated and administration is at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, February, 75 May be separated until Sunday, March, or June.

  In certain embodiments, the compound provided herein, and the second agent, have an increased benefit over the compound provided herein acting with other agents to administer them separately. It can be administered to a patient, eg, a mammal such as a human, in order and at certain time intervals so that it can be provided. For example, the second active agents can be administered simultaneously, or sequentially in any order at different locations in time; however, if not administered simultaneously, they may have the desired therapeutic effect or prophylaxis. It should be administered close enough in a timely manner to provide an effect. In one embodiment, the compounds provided herein and the second active agent exert their effects when they overlap. Each second active agent can be administered separately in any suitable form and by any suitable route. In other embodiments, the compound provided herein is administered before, simultaneously with, or after administration of the second active agent.

  In certain embodiments, the compound provided herein and the second agent are administered periodically to the patient. Cycling therapy includes the administration of a first agent (eg, a first prophylactic or therapeutic agent) for a while, followed by a second agent and / or a third agent (eg, a second agent) for a while. And / or a third prophylactic or therapeutic agent) and repeat this continuous administration. Cycling therapy can reduce the onset of resistance to one or more of the therapies, can avoid or reduce one side effect of the therapy, and / or improve the effectiveness of the treatment .

  In certain embodiments, the compound provided herein and the second active agent are less than about 3 weeks, about once every 2 weeks, about once every 10 days, or about every 1 week. It is administered in a cycle. One cycle can include administration of a compound provided herein and a second agent by infusion over about 90 minutes per cycle, about 1 hour per cycle, about 45 minutes per cycle. Each cycle can include at least one week of rest, at least two weeks of rest, and at least three weeks of rest. The number of cycles administered is from about 1 to about 12 cycles, more typically from about 2 to about 10 cycles, more typically from about 2 to about 8 cycles.

  In other embodiments, the course of treatment is administered to the patient simultaneously, i.e., the individual dose of the second agent is such that the compound provided herein can work with the second active agent. Are further administered separately within a given interval. For example, one component can be administered once every week, in combination with other components that can be administered once every two weeks, or once every three weeks. In other words, the dosing regimen is performed at the same time, even if treatment is not administered at the same time or during the same day.

  The second agent can act additively or synergistically with the compounds provided herein. In one embodiment, the compound provided herein is administered concurrently with one or more second agents in the same pharmaceutical composition. In another embodiment, the compounds provided herein are administered concurrently with one or more second agents in separate pharmaceutical compositions. In yet another embodiment, the compound provided herein is administered before or after administration of the second agent. Also contemplated are administration of the compound provided herein and a second agent by the same or different routes of administration, eg, oral and parenteral. In certain embodiments, when a compound provided herein is administered concurrently with a second agent that potentially produces adverse side effects, including but not limited to toxicity, the second active agent is detrimental. Can be conveniently administered at a dose that falls below the threshold at which adverse side effects are induced.

(kit)
Also provided are kits for use in methods of treating liver disorders such as HCV and / or HBV infection. The kit can include a compound or composition provided herein, a second agent or composition, and instructions that provide a health care provider with information regarding use to treat the disorder. The instructions may be provided in printed form or in the form of an electronic medium such as a floppy disk, CD, or DVD, or in the form of a website address from which such instructions may be obtained. A unit dose of a compound or composition provided herein, or a second agent or composition, includes a therapeutically prophylactically effective plasma level of the compound or composition when administered to a subject. The dosage can be maintained in the subject for at least 1 day. In some embodiments, the compound or composition can be included as a sterile aqueous pharmaceutical composition, or a dry powder (eg, lyophilized) composition.

  In some embodiments, suitable packaging is provided. As used herein, “packaging” refers to a fixed delimitation of a compound provided herein and / or a second agent that is conventionally used in the system and suitable for administration to a subject. Includes a solid matrix, or material, that can be retained within. Such materials include glass and plastic (eg, polyethylene, polypropylene, and polycarbonate), bottles, vials, paper, plastic, and plastic-foil laminate envelopes, and the like. If e-beam sterilization techniques are used, the packaging should have a sufficiently low density to allow sterilization of the contents.

  The following examples illustrate the synthesis of representative compounds provided herein. These examples are not intended to limit the scope of the claimed subject matter and are not to be construed as limiting. It will be apparent that the scope of claimed subject matter may be practiced otherwise than as specifically described herein. Many modifications of the subject matter are possible in light of the teachings herein and are therefore within the scope of the claimed subject matter.

合成スキーム：

カルボン酸2の合成：

2,2-ジメチル-3-ヒドロキシプロパン酸メチルエステル（965μL、7.57mmol）を室温にてピリジン無水物（7.6mL）中の4,4'-ジメトキシトリチルクロリド（2.82g、8.33mmol）の撹拌溶液に滴下した。反応混合物は、急速に赤い溶液に、次いでオレンジの懸濁液（およそ30分）に変わり、これを一晩撹拌したままにしておいた。混合物を飽和NaHCO₃水溶液（30mL）上に慎重に注いで、生成物をEt₂O（3×20mL）で抽出した。合わせた有機抽出物を鹹水（20mL）で洗浄し、乾燥（Na₂SO₄）させ、揮発性物質を減圧下で除去した。生じる油をトルエンと共に蒸発させて、残渣を5→10→20→30% Et₂Oの石油エーテル（40-60）溶液で溶出するフラッシュカラムクロマトグラフィー（SiO₂、φ= 4cm、H = 20cm）によって迅速に精製した。画分（R_f= 0.25、30% Et₂Oの石油エーテル溶液（40-60））の蒸発により、黄色の油（3.11g、95%）としてエーテル1を得た。この化合物（3.00g、6.91mmol）をTHF（35mL）に溶解して、次いでNaOHの水溶液（10%、35mL H₂O中の3.5g）を室温で添加した。溶液は、すぐに暗いオレンジに変化し、これを2日間撹拌した。次いで、HCl（1M）の滴状添加によって、培地を慎重に中和した。生成物をEt₂O（4×50mL）で抽出して、合わせた有機抽出物を鹹水（50mL）で洗浄し、乾燥（Na₂SO₄）させて、揮発性物質を減圧下で除去した。粗製黄色油を、石油エーテル（40-60）中の50%のEt₂Oで溶出するフラッシュカラムクロマトグラフィー（SiO₂、φ= 2cm、H = 10cm）によって迅速に精製した。画分の蒸発により、白い泡（2.23g、77%）としてカルボン酸2を得た。R_f= 0.50（石油エーテル（40-60）中の50%のEt₂O）；

(Example 1)
Preparation of hydroxy-tBuSATE N-benzyl phosphoramidate derivative of A550 (NM204), L-2 ', 3'-dideoxyadenosine L-ddA

Synthesis scheme:

Synthesis of carboxylic acid 2:

2,2-Dimethyl-3-hydroxypropanoic acid methyl ester (965 μL, 7.57 mmol) at room temperature in 4,4′-dimethoxytrityl chloride (2.82 g, 8.33 mmol) in pyridine anhydride (7.6 mL) It was dripped in. The reaction mixture quickly turned to a red solution and then to an orange suspension (approximately 30 minutes), which was left stirring overnight. The mixture was carefully poured onto saturated aqueous NaHCO ₃ (30 mL) and the product was extracted with Et ₂ O (3 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried (Na ₂ SO ₄ ) and volatiles were removed under reduced pressure. Evaporate the resulting oil with toluene and flash column chromatography eluting with 5 → 10 → 20 → 30% Et ₂ O in petroleum ether (40-60) (SiO ₂ , φ = 4cm, H = 20cm) Quickly purified by. Evaporation of the fraction (R _f = 0.25, 30% Et ₂ O in petroleum ether (40-60)) gave ether 1 as a yellow oil (3.11 g, 95%). This compound (3.00 g, 6.91 mmol) was dissolved in THF (35 mL) and then an aqueous solution of NaOH (10%, 3.5 g in 35 mL H ₂ O) was added at room temperature. The solution immediately turned dark orange and was stirred for 2 days. The medium was then carefully neutralized by the dropwise addition of HCl (1M). The product was extracted with Et ₂ O (4 × 50 mL) and the combined organic extracts were washed with brine (50 mL), dried (Na ₂ SO ₄ ) and volatiles were removed under reduced pressure. The crude yellow oil was rapidly purified by flash column chromatography (SiO ₂ , φ = 2 cm, H = 10 cm) eluting with 50% Et ₂ O in petroleum ether (40-60). Evaporation of the fractions gave carboxylic acid 2 as a white foam (2.23 g, 77%). R _f = 0.50 (50% Et ₂ O in petroleum ether (40-60));

1,1'-カルボニルジイミダゾール（830mg、5.12mmol）をPhMe/DMF無水物（2/1、v/v、2.7mL）中のカルボン酸2の撹拌溶液に室温で添加し、反応混合物は、すぐに濁りを生じた。30分後、培地をPhMe/DMF無水物（93/7、v/v、17mL）を添加することによって希釈して、次いで-10℃まで冷却した。2-メルカプトエタノール（359μL、5.12mmol）を滴状に添加して、溶液をこの温度にて1時間撹拌した。反応混合物をH₂O（60mL）で希釈して、生成物をEt₂O（3×15mL）で抽出した。合わせた有機抽出物を鹹水（15mL）で洗浄し、乾燥（Na₂SO₄）させて、揮発性物質を減圧下で除去した（20℃を上回らない浴温）。残渣を60→70% Et₂Oの石油エーテル（40-60）溶液で溶出するフラッシュカラムクロマトグラフィー（SiO₂、φ= 4cm、H = 15cm、1% Et₃N）によって精製した。画分の蒸発により、白いシロップ（1.74g、92%）として、チオエステル3を得て、4℃にて貯蔵することにより、凝固した。R_f= 0.35（石油エーテル（40-60）中の70% Et₂O）；

Synthesis of thioester 3:

1,1′-carbonyldiimidazole (830 mg, 5.12 mmol) was added to a stirred solution of carboxylic acid 2 in PhMe / DMF anhydride (2/1, v / v, 2.7 mL) at room temperature and the reaction mixture was Immediately cloudy. After 30 minutes, the medium was diluted by adding PhMe / DMF anhydrous (93/7, v / v, 17 mL) and then cooled to −10 ° C. 2-mercaptoethanol (359 μL, 5.12 mmol) was added dropwise and the solution was stirred at this temperature for 1 hour. The reaction mixture was diluted with H ₂ O (60 mL) and the product was extracted with Et ₂ O (3 × 15 mL). The combined organic extracts were washed with brine (15 mL), dried (Na ₂ SO ₄ ) and volatiles were removed under reduced pressure (bath temperature not exceeding 20 ° C.). The residue was purified by flash column chromatography (SiO ₂ , φ = 4 cm, H = 15 cm, 1% Et ₃ N) eluting with 60 → 70% Et ₂ O in petroleum ether (40-60). Evaporation of the fractions gave the thioester 3 as a white syrup (1.74 g, 92%), which solidified by storage at 4 ° C. R _f = 0.35 (70% Et ₂ O in petroleum ether (40-60));

β-L-ddA（1.00g、4.25mmol）をピリジン無水物（3×10mL）と共に同時蒸発させて、次いで、ピリジン/DMF無水物（1/1、v/v、21mL）に溶解させた。次いで、この溶液に亜リン酸ジフェニル（5.76mL、29.8mmol）を室温で滴下した。反応混合物を20分間撹拌して、これにEt₃N/H₂O（1/1、v/v、8.5mL）の混合物を滴状に添加して、攪拌を更に20分間続けた。反応混合物をおよそ15-20mLまで減圧下で濃縮して、この残渣をCH₂Cl₂（150mL）、次いでCH₂Cl₂中の5%（200mL）→10%（200mL）→15%（300mL）MeOHでゆっくりと溶出するフラッシュカラムクロマトグラフィー（SiO₂、φ= 4cm、H =15cm、1% Et₃N）によって直接精製した。画分の蒸発により、白い泡（1.36g、80%）として、H-ホスホナートモノエステル4を得て、4℃にて数週間保持することができた。

Synthesis of H-phosphonate monoester 4:

β-L-ddA (1.00 g, 4.25 mmol) was co-evaporated with pyridine anhydride (3 × 10 mL) and then dissolved in pyridine / DMF anhydride (1/1, v / v, 21 mL). Then, diphenyl phosphite (5.76 mL, 29.8 mmol) was added dropwise to this solution at room temperature. The reaction mixture was stirred for 20 minutes, to which a mixture of Et ₃ N / H ₂ O (1/1, v / v, 8.5 mL) was added dropwise and stirring was continued for another 20 minutes. The reaction mixture is concentrated under reduced pressure to approximately 15-20 mL and the residue is CH ₂ Cl ₂ (150 mL), then 5% (200 mL) → 10% (200 mL) → 15% (300 mL) in CH ₂ Cl _2. Purified directly by flash column chromatography (SiO ₂ , φ = 4 cm, H = 15 cm, 1% Et ₃ N) eluting slowly with MeOH. Evaporation of the fractions gave H-phosphonate monoester 4 as white foam (1.36 g, 80%), which could be kept at 4 ° C. for several weeks.

H-ホスホナートモノエステル4（1.03g、2.57mmol）、及びアルコール3（1.66g、3.45mmol）をピリジン無水物（3×5mL）と共に同時蒸発させて、次いでピリジン無水物（5mL）に溶解した。次いで、PyBOP（1H-ベンゾトリアゾール-1-イルオキシトリピロリジノホスホニウムヘキサフルオロホスフェート、1.60g、3.08mmol）を一部分添加して、反応混合物を室温で15分間撹拌した。溶液を飽和NaHCO₃水溶液（30mL）に注いで、生成物をCH₂Cl₂（4×15mL）で抽出した。合わせた有機抽出物を鹹水（10mL）で洗浄し、乾燥（Na₂SO₄）させて、減圧下で濃縮し、わずかに黄色の油（1.84g、2.41mmolと推定）として対応するH-ホスホナートジエステルを残した。これをピリジン無水物と共に同時蒸発させて（3×5mL；注：さらなる可溶化を補助するために乾燥までは蒸発させない）、残渣をCCl₄無水物（24mL）に溶解した。ベンジルアミン（791μL、7.23mmol）を滴状に添加して、反応混合物がすぐに濁った（わずかな熱発が観察された）。乳状の溶液を室温で1時間撹拌して、飽和NaHCO₃水溶液（30mL）上に注いで、生成物をCH₂Cl₂（4×15mL）で抽出した。合わせた有機抽出物を鹹水（15mL）で洗浄し、乾燥（Na₂SO₄）させて、減圧下で濃縮し、黄色の油（2.00g、2.31mmolと推定）としてホスホラミダートジエステル5を得た。これを、任意のさらなる精製を伴わずに次の工程に使用した。R_f = 0.29（CH₂Cl₂中の4% MeOH）；

Synthesis of phosphoramidate diester 5.

H-phosphonate monoester 4 (1.03 g, 2.57 mmol), and alcohol 3 (1.66 g, 3.45 mmol) were coevaporated with pyridine anhydride (3 × 5 mL) and then dissolved in pyridine anhydride (5 mL) . PyBOP (1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate, 1.60 g, 3.08 mmol) was then added in one portion and the reaction mixture was stirred at room temperature for 15 minutes. The solution was poured into saturated aqueous NaHCO ₃ (30 mL) and the product was extracted with CH ₂ Cl ₂ (4 × 15 mL). The combined organic extracts were washed with brine (10 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give the corresponding H-phospho as a slightly yellow oil (1.84 g, estimated to be 2.41 mmol). The narate diester was left. This was coevaporated with pyridine anhydride (3 × 5 mL; Note: not evaporated to dryness to aid further solubilization) and the residue was dissolved in CCl ₄ anhydride (24 mL). Benzylamine (791 μL, 7.23 mmol) was added dropwise and the reaction mixture became cloudy immediately (a slight fever was observed). The milky solution was stirred at room temperature for 1 h, poured onto saturated aqueous NaHCO ₃ (30 mL) and the product was extracted with CH ₂ Cl ₂ (4 × 15 mL). The combined organic extracts are washed with brine (15 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give phosphoramidate diester 5 as a yellow oil (2.00 g, estimated to be 2.31 mmol). It was. This was used in the next step without any further purification. R _f = 0.29 (4% MeOH in CH ₂ Cl ₂ );

粗製ホスホラミダートジエステル5（2.00g、2.31mmolと推定）をジオキサン/AcOH/H₂O（25/17/25、v/v/v、462mL）に溶解して、溶液を室温で3日間撹拌した。減圧下での揮発性物質の蒸発により、残渣を残し、CH₂Cl₂（100mL）、次いでCH₂Cl₂中の2%（100mL）→4%（100mL）→6%（100mL）→8%（150mL）MeOHで溶出するフラッシュカラムクロマトグラフィー（SiO₂、φ= 3cm、H = 15cm）によって精製した。画分の蒸発により、白い泡としてNM 204を残し、これをMeCN（5mL）に溶解した。H₂O（5mL）の添加により、溶液が濁りを生じ、凍結乾燥前に超音波処理を必要とした。生じる白色粉末を1日間真空下で室温にて乾燥させた（乾燥剤としてP₂OK₅を使用）。表題化合物は、高度に吸湿性の白色粉末として得られた（³¹P-NMRによる判断としてジアステレオ異性体の1：1の混合物；499mg、3工程にわたって35%）。

Synthesis of hydroxy-tBuSATE N-benzyl phosphoramidate derivative of NM204 (A550), L-ddA:

Crude phosphoramidate diester 5 (2.00 g, estimated to be 2.31 mmol) was dissolved in dioxane / AcOH / H ₂ O (25/17/25, v / v / v, 462 mL) and the solution was stirred at room temperature for 3 days did. Evaporation of volatiles under reduced pressure leaves a residue, CH ₂ Cl ₂ (100 mL), then 2% (100 mL) in CH ₂ Cl ₂ → 4% (100 mL) → 6% (100 mL) → 8% Purified by flash column chromatography (SiO ₂ , φ = 3 cm, H = 15 cm) eluting with (150 mL) MeOH. Evaporation of the fractions left NM 204 as a white foam that was dissolved in MeCN (5 mL). The addition of H ₂ O (5 mL) caused the solution to become turbid and required sonication before lyophilization. The resulting white powder was dried at room temperature under vacuum for 1 day (using P ₂ OK ₅ as the desiccant). The title compound was obtained as a highly hygroscopic white powder (1: 1 mixture of diastereoisomers as judged by ³¹ P-NMR; 499 mg, 35% over 3 steps).

手順A：
H-ホスホナートモノエステル5の合成：

カルボン酸3の合成：
塩化メチレン無水物（590mL）、及びトリエチルアミン（23mL）の混合物中の2,2-ジメチル-3-ヒドロキシプロパン酸メチルエステル（1、15mL、117.6mmol）の撹拌溶液に、トリフェニルメチレンクロリド（1.2eq、39.3g）、及び4-ジメチルアミノピリジン（0.1eq、1.44g）を添加した。反応混合物を一晩還流したままにしておいた。混合物を飽和NaHCO₃水溶液上に慎重に注いで、生成物を塩化メチレンで抽出して、水で洗浄した。合わせた有機抽出物を減圧下で蒸発させ、粗製化合物2を得て、これをに更に精製することなく次の工程のために使用する。生じる油をジオキサン（350mL）、及びNaOH水溶液（30%、350mL）の混合物に溶解した。不均一混合物を16時間還流した。反応混合物を室温に冷却させて、二相に分離して、有機相を、HCl（1M）を滴状に添加することによって慎重に中和した。生成物を塩化メチレンで抽出して、有機相を減圧下で蒸発させた。粗製オレンジ油を塩化メチレンから再結晶し、白い結晶（92%）としてカルボン酸3を得た。R_f= 0.50（石油エーテル中の70% ジエチルエーテル）；

(Example 2)
Preparation of hydroxy-tBuSATE N-benzyl phosphoramidate derivative of B102, 2'-C-methylcytidine:

Step A:
Synthesis of H-phosphonate monoester 5:

Synthesis of carboxylic acid 3:
To a stirred solution of 2,2-dimethyl-3-hydroxypropanoic acid methyl ester (1, 15 mL, 117.6 mmol) in a mixture of methylene chloride anhydride (590 mL) and triethylamine (23 mL) was added triphenylmethylene chloride (1.2 eq). 39.3 g) and 4-dimethylaminopyridine (0.1 eq, 1.44 g) were added. The reaction mixture was left at reflux overnight. The mixture was carefully poured onto saturated aqueous NaHCO ₃ and the product was extracted with methylene chloride and washed with water. The combined organic extracts are evaporated under reduced pressure to give crude compound 2, which is used for the next step without further purification. The resulting oil was dissolved in a mixture of dioxane (350 mL) and aqueous NaOH (30%, 350 mL). The heterogeneous mixture was refluxed for 16 hours. The reaction mixture was allowed to cool to room temperature, separated into two phases, and the organic phase was carefully neutralized by the dropwise addition of HCl (1M). The product was extracted with methylene chloride and the organic phase was evaporated under reduced pressure. The crude orange oil was recrystallized from methylene chloride to give carboxylic acid 3 as white crystals (92%). R _f = 0.50 (70% diethyl ether in petroleum ether);

Synthesis of H-phosphonate monoester 5:
1,1′-carbonyldiimidazole (1.3 eq, 1.17 g) at room temperature with carboxylic acid 3 (2 g, 5.56 mmol) in an anhydrous mixture of toluene and dimethylformamide (2/1, v / v, 4.5 mL) The reaction mixture immediately became cloudy. After 30 minutes, the reaction mixture was diluted with a mixture of toluene and dimethylformamide (93/7, v / v, 28 mL), cooled to −10 ° C., and 2-mercaptoethanol (1.3 eq, 500 μL) was added. . The solution was stirred at this temperature for 3 hours. Volatiles were removed under reduced pressure (bath temperature not exceeding 25 ° C.). The residue was dissolved in methylene chloride and washed with water. The organic phases were combined, dried over sodium sulfate (Na ₂ SO ₄ ), filtered and evaporated to dryness to give compound 4 as a yellow oil. This compound is coevaporated with pyridine anhydride and used for the next step without further purification. R _f = 0.71 (70% Et ₂ O in petroleum ether);

Phosphoric acid (10 eq, 4.1 g) was co-evaporated twice with pyridine anhydride, dissolved in the solvent (25 mL) and added to crude 4. The reaction mixture was stirred at room temperature and a white precipitate was visible after a few minutes. The reaction mixture was cooled to 0 ° C. and pivaloyl chloride (5.5 eq, 3.4 mL) was added. The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction was stopped by the addition of a solution of triethylammonium bicarbonate (TEAB 1M, 10 mL) and diluted with ethyl acetate (EtOAc). After extraction with 0.5M EtOAc and TEAB, the organic phases were combined, dried over sodium sulfate, filtered and evaporated to dryness (bath temperature not exceeding 30 ° C.). The residue was purified by flash column chromatography eluting with 10% methanol in methylene chloride + 1% triethylamine. Evaporation of the fractions gave H-phosphonate monoester 5 as a white syrup (90%). R _f = 0.25 (70% Et ₂ O in petroleum ether);

2'C-メチルシチジン（NM107）（10g、39.0mmol）、オルトギ酸トリエチル（8.3eq、54mL）、及びpトルエンスルホン酸一水和物（1eq、7.4g）のアセトン無水物（650mL）中の混合物を、窒素雰囲気下で一晩還流した。反応混合物をアンモニア水溶液（26%）で中和して、沈殿物を濾過した。濾液を減圧下で蒸発させて、エタノールと共に同時蒸発させた。シリカゲルカラムクロマトグラフィーでの粗製混合物の精製（溶出剤：塩化メチレン中のメタノールの段階勾配[0-10%])により、淡黄色の固体（86%）として、化合物6を生じた。R_f= 0.30（塩化メチレン中の20% MeOH）、

Synthesis of hydroxy-tBuSATE N-benzyl phosphoramidate derivatives of B102, 2'-C-methylcytidine:
The following two strategies were used:
Strategy a
Synthesis of protected nucleoside 7

2'C-methylcytidine (NM107) (10 g, 39.0 mmol), triethyl orthoformate (8.3 eq, 54 mL), and p-toluenesulfonic acid monohydrate (1 eq, 7.4 g) in acetone anhydride (650 mL) The mixture was refluxed overnight under a nitrogen atmosphere. The reaction mixture was neutralized with aqueous ammonia (26%) and the precipitate was filtered. The filtrate was evaporated under reduced pressure and coevaporated with ethanol. Purification of the crude mixture by silica gel column chromatography (eluent: step gradient of methanol in methylene chloride [0-10%]) gave compound 6 as a pale yellow solid (86%). R _f = 0.30 (20% MeOH in methylene chloride),

Compound 6 (4.4 g, 14.8 mmol) was dissolved in pyridine anhydride (74 mL) and chlorotrimethylsilane (3 eq, 5.4 mL) was added. The reaction mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere and then 4,4′-dimethoxytrityl chloride (1.5 eq, 7.5 g) and 4-dimethylaminopyridine (0.5 eq, 900 mg) were added sequentially. . The reaction mixture was stirred at room temperature overnight and then quenched with saturated aqueous NaHCO ₃ solution. The crude product was extracted with methylene chloride and washed with saturated aqueous NaHCO ₃ and water. The combined organic layers were concentrated under reduced pressure and then dissolved in a mixture of dioxane (160 mL) and aqueous ammonia (28%, 29 mL). The solution was heated at 70 ° C. for 3 hours and evaporated to dryness. The crude mixture was purified by silica gel column chromatography (eluent: step gradient of methanol [1-5%] in methylene chloride) to give protected nucleoside 7 as a yellow solid (81%). R _f = 0.16 (30% EtOAc in CH ₂ Cl ₂ ),

化合物7（2.0g、3.34mmol）、及び5（2.2eq、4.3g）を、ピリジン無水物と共に同時蒸発させて、この溶媒（50mL）に溶解した。塩化ピバロイル（2.5eq、1mL）を滴状に添加して、溶液を2時間30分間室温で撹拌した。反応混合物を塩化メチレンで希釈して、塩化アンモニウム水溶液（0.5M NH₄Cl）で中和した。0.5M塩化メチレン/水溶液NH₄Clで抽出後、有機相を合わせて、減圧下で蒸発させて（30℃を上回らない浴温）、トルエンと共に同時蒸発させた。粗製混合物をシリカゲルカラムクロマトグラフィーで精製し（溶出剤：塩化メチレン+ 2‰酢酸中のメタノールの段階勾配[0-5%])、所望の生成物8を得て、これをトルエンと共に同時蒸発させて、ベージュの泡（94%）を得た。R_f = 0.63（CH₂Cl₂中の5% MeOH）；

Synthesis B102 (Compound 10)

Compound 7 (2.0 g, 3.34 mmol) and 5 (2.2 eq, 4.3 g) were coevaporated with pyridine anhydride and dissolved in this solvent (50 mL). Pivaloyl chloride (2.5 eq, 1 mL) was added dropwise and the solution was stirred for 2 h 30 min at room temperature. The reaction mixture was diluted with methylene chloride and neutralized with aqueous ammonium chloride (0.5M NH ₄ Cl). After extraction with 0.5M methylene chloride / aq NH ₄ Cl, the organic phases were combined, evaporated under reduced pressure (bath temperature not exceeding 30 ° C.) and co-evaporated with toluene. The crude mixture is purified by silica gel column chromatography (eluent: methylene chloride + step gradient of methanol in 2 ‰ acetic acid [0-5%]) to give the desired product 8, which is coevaporated with toluene. Of beige foam (94%). R _f = 0.63 (5% MeOH in CH ₂ Cl ₂ );

A solution of compound 8 (3.4 g, 3.15 mmol) in carbon tetrachloride anhydride (30 mL) was added dropwise to benzylamine (10 eq, 3.4 mL). The reaction mixture was stirred for 1 hour 30 minutes at room temperature. A white precipitate appeared. The solution was diluted with methylene chloride and neutralized with an aqueous solution of hydrogen chloride (HCl 1M). After sequential extraction with CH ₂ Cl ₂ / HCl 1M and CH ₂ Cl ₂ / aq NaHCO ₃ , the organic phases were combined, dried over Na ₂ SO ₄ , filtered and evaporated to dryness. The crude mixture was purified by silica gel column chromatography (eluent: step gradient of methanol in methylene chloride [0-5%]) to give 9 as a yellow foam (87%). R _f = 0.35 (5% MeOH in methylene chloride);

Finally, compound 9 (2.39 g, 2.04 mmol) was dissolved in a mixture of methylene chloride (10 mL) and an aqueous solution of trifluoroacetic acid (90%, 10 mL). The reaction mixture was stirred at 35-40 ° C. for 2 hours and then diluted with ethanol (140 mL). Volatiles were evaporated under reduced pressure and co-evaporated with ethanol. The crude mixture was purified by silica gel column chromatography (eluent: step gradient of methanol [0-30%] in methylene chloride) followed by reverse phase chromatography (eluent: acetonitrile in water [0-50] %] Step gradient) to give the desired product 10 (B102) (1: 1 mixture of diastereoisomers as judged by ³¹ P-NMR), which was lyophilized from a dioxane / water mixture. . R _f = 0.34 (15% MeOH in methylene chloride);

NM107（10g、38.87mmol）をピリジン無水物（194mL）に溶解して、クロロトリメチルシラン（4.5eq、21.6mL）を添加した。反応混合物を窒素雰囲気下で室温にて2時間30分間撹拌し、次いで4,4'-ジメトキシトリチルクロリド（1.5eq、19.8g）、及び4-ジメチルアミノピリジン（0.5eq、2.37g）を連続して添加した。反応混合物を室温で一晩撹拌して、次いで飽和NaHCO₃水溶液でクエンチした。粗生成物を塩化メチレンで抽出し、飽和NaHCO₃水溶液、及び水で洗浄した。合わせた有機層を減圧下で濃縮して、次いでテトラヒドロフラン（110mL）に溶解した。その溶液に、THF（1eq、38.87mL）中のフッ化テトラブチルアンモニウム1Mを添加して、反応混合物を室温で30分間撹拌した。EtOAc、及び水で抽出後、有機相を収集して、乾燥まで蒸発させた。粗製混合物をシリカゲルカラムクロマトグラフィーで精製し（溶出剤：塩化メチレン中のメタノール[0-10%］の段階勾配）、黄色の固体（93%）として保護されたヌクレオシド11を得た。R_f= 0.32（CH₂Cl₂中の10% MeOH）、

Strategy b: Synthesis of protected nucleoside 11

NM107 (10 g, 38.87 mmol) was dissolved in pyridine anhydride (194 mL) and chlorotrimethylsilane (4.5 eq, 21.6 mL) was added. The reaction mixture was stirred at room temperature for 2 hours 30 minutes under a nitrogen atmosphere, then 4,4′-dimethoxytrityl chloride (1.5 eq, 19.8 g) and 4-dimethylaminopyridine (0.5 eq, 2.37 g) were successively added. Added. The reaction mixture was stirred at room temperature overnight and then quenched with saturated aqueous NaHCO ₃ solution. The crude product was extracted with methylene chloride and washed with saturated aqueous NaHCO ₃ and water. The combined organic layers were concentrated under reduced pressure and then dissolved in tetrahydrofuran (110 mL). To the solution was added tetrabutylammonium fluoride 1M in THF (1 eq, 38.87 mL) and the reaction mixture was stirred at room temperature for 30 minutes. After extraction with EtOAc and water, the organic phase was collected and evaporated to dryness. The crude mixture was purified by silica gel column chromatography (eluent: step gradient of methanol [0-10%] in methylene chloride) to give the protected nucleoside 11 as a yellow solid (93%). R _f = 0.32 (10% MeOH in CH ₂ Cl ₂ ),

化合物11（7g、12.5mmol）、及び5（1.5eq、11.0g）を、ピリジン無水物と共に同時蒸発させて、この溶媒（187mL）に溶解した。塩化ピバロイル（2.0eq、3.08mL）を-15℃にて滴状に添加し、溶液をこの温度にて1時間30分間撹拌した。反応混合物を塩化メチレンで希釈して、塩化アンモニウムの水溶液（0.5M NH₄Cl）で中和した。0.5M塩化メチレン/水溶液NH₄Clで抽出後、有機相を合わせて、減圧下で蒸発させて（30℃を上回らない浴温）、トルエンと共に同時蒸発させた。粗製混合物をシリカゲルカラムクロマトグラフィーで精製し（溶出剤：塩化メチレン+ 0.2%酢酸中のメタノールの段階勾配[0-5%])、所望の生成物12を得て、これをトルエンと共に同時蒸発させ、白い泡（3.5g、27%）を得た。R_f= 0.44（CH₂Cl₂中の5% MeOH）；

Synthesis of protected phosphoramidate pronucleotide 13 as ten precursors

Compounds 11 (7 g, 12.5 mmol), and 5 (1.5 eq, 11.0 g) were coevaporated with pyridine anhydride and dissolved in this solvent (187 mL). Pivaloyl chloride (2.0 eq, 3.08 mL) was added dropwise at -15 ° C. and the solution was stirred at this temperature for 1 hour 30 minutes. The reaction mixture was diluted with methylene chloride and neutralized with an aqueous solution of ammonium chloride (0.5M NH ₄ Cl). After extraction with 0.5M methylene chloride / aq NH ₄ Cl, the organic phases were combined, evaporated under reduced pressure (bath temperature not exceeding 30 ° C.) and co-evaporated with toluene. The crude mixture is purified by silica gel column chromatography (eluent: methylene chloride + step gradient of methanol in 0.2% acetic acid [0-5%]) to give the desired product 12, which is coevaporated with toluene. White foam (3.5 g, 27%) was obtained. R _f = 0.44 (5% MeOH in CH ₂ Cl ₂ );

To a solution of compound 12 (500 mg, 0.49 mmol) in carbon tetrachloride anhydride (4.9 mL) was added benzylamine (5 eq, 0.266 mL) dropwise. The reaction mixture was stirred at room temperature for 3 hours and the solvent was removed under reduced pressure. The crude mixture was purified by silica gel column chromatography (eluent: step gradient of methanol in methylene chloride [0-5%]) to give compound 13 as a foam (75%). R _f = 0.25 (3% MeOH in methylene chloride);

  Compound 13 can be converted to phosphoramidate prodrug 10 (B102) according to the experimental conditions described in Example 3 (Procedure A) and in Example 4 for the final step.

合成スキーム：
B102は、1：1の比で亜リン酸ジアステレオマーの混合物として合成される。生成された全ての結合された材料を脱保護のために使用したわけではなかったので、NM107からB102への単離された全収率は、31%であった。
工程1.1：

Step B:

Synthesis scheme:
B102 is synthesized as a mixture of phosphite diastereomers in a 1: 1 ratio. The total isolated yield from NM107 to B102 was 31% since not all the bound material produced was used for deprotection.
Step 1.1:

NM107 was dissolved in pyridine under argon and benzeneboronic acid was added. The stirred mixture was heated at reflux for 3 hours under argon. The azeotrope was then distilled to remove 1.2 L (pyridine / water).
T head: 103 ° C → 113 ° C T mixture: 112 ° C → 116 ° C
The mixture was cooled to room temperature and pyridine was evaporated under vacuum to give a golden oil. The product was stored under vacuum overnight for use in the next step. A 97: 3 product: starting material ratio was observed by 1H-NMR (d6-DMSO). Prior to step 1.2, the crude was dissolved in 25OmL pyridine anhydride. Alternatively, the following conditions may be used:
-eq benzeneboronic acid
-5 eq pyridine
-1.5 eq Na ₂ SO ₄
5mL CH ₃ CN for -1g NM107
-1 hour-1 hour 30 minutes at reflux. Cool to RT. Used for next reaction.
-98-99% conversion by proton NMR.
Step 1.2:

  Phosphonate 3 was dissolved in 3 L acetonitrile under argon. A solution of 2,3-PhB-NM 107 from step 1.1 was added and EDCI.HCl was added. The mixture was stirred at 41-46 ° C. under argon for 4 hours, after which time HPLC analysis indicated a ratio of P—H product to NM107 of ˜7: 1. The mixture was cooled to 18 ° C. and benzylamine was added dropwise followed by carbon tetrachloride. The reaction was slightly exothermic. Analysis by HPLC showed complete conversion of P-H to the phosphoramidate product. Ethyl acetate (1 L) was added to the mixture and then acidified to pH 4 with 3 L of 20% citric acid. The aqueous phase was extracted with 2.5 L ethyl acetate. The organic phases were combined and washed with 3 L of 10% citric acid. The organic phase was basified to pH 8 with 5 L aqueous sodium bicarbonate (saturated) and washed a second time with 2 L aqueous sodium bicarbonate (saturated). The organic phase was dried over sodium sulfate, filtered under vacuum and evaporated to give a yellow foam (712g).

The crude residue was dissolved in dichloromethane (1 L) and purified with a silica plug (2.3 kg of silica). Elute with 5L 4% methanol / DCM, 2 * 1L 4%, 3 * 1L 5%, 8 * 250mL 6%, 4 * 250mL 7%, 9 * 1L 7%. Evaporation of the relevant fractions gave 254 g (HPLC purity: 98.5%, yield: 52%) and 73 g (HPLC purity: 87.6%, yield: 13%) phosphoramidate 4.
Process 2:

Phosphoramidate 4 was dissolved in ethanol anhydride and acetyl chloride was added to the reaction mixture under argon (exothermic: 18 ° C. to 27 ° C.). The mixture was stirred at 60 ° C. under argon. After 30 minutes, HPLC analysis showed complete conversion of phosphoramidate 4 to deprotected product 5. The mixture was cooled to 25 ° C. and solid sodium bicarbonate (1.04 kg) was added to several portions (foaming, pH˜5.5-6). The mixture was filtered through celite and washed with 2 volumes of ethanol. The filtrate was evaporated at 35 ° C. under vacuum. The residue was triturated with TBME (3 L) for 1 hour and then filtered to remove the trityl byproduct. The resulting solid was dried under vacuum to give 185 g with 93% purity at 254 nm by HPLC.
If necessary, any residual benzeneboronic acid may be removed from the product by dissolving in water and treated with Amberlite IRA-743 resin.
The following alternative reaction conditions (to avoid the possibility of acylation 4) are also possible:
-2.0eq EtCl solution of AcCl 1:10 v: v generates HCl and consumes all AcCl (exothermic)
-EtOH solution of phosphoramide 4 (1: 10 w: v total volume EtOH is made)
-Add HCl / EtOH solution to the reaction mixture at 20 ° C
-6O ° C, 30-45 minutes under argon.
The crude was purified by reverse phase chromatography (1.5 Kg prepared Bakerbond 40 μm C-18 RP-silica-100% acetonitrile to 100% H ₂ O gradient wash). The crude was dissolved in acetonitrile (58 mL), H ₂ O (164 mL), and saturated aqueous sodium bicarbonate (17 OmL). _{3% MeCN / H 2 0,10%} , 15%, elution under mild vacuum by 25% step gradient (pure product was eluted), and evaporation of the appropriate number of fractions, the 254nm by HPLC Gave 106 g B102 (62% yield) in 98.6% purity.
Typical analysis data is shown below:

  Synthetic procedure A can be used to synthesize nucleoside prodrugs such as B102. Protection of 2 'and 3' hydroxyl groups, which may be present on the nucleoside base, as well as amino groups is preferred. In strategy A, the 2 ′ and 3 ′ hydroxyl groups are protected, for example, as acetonide derivatives, and the amino group, for example, as a dimethoxytrityl derivative. The hydrolysis of acteonide after the coupling of the SATE intermediate and the nucleoside is carried out using an acid such as TFA. This hydrolysis procedure can produce by-products and shows low yields, and dimethoxytrityl chloride is disadvantageously expensive. Synthetic procedure B, below, can overcome such difficulties. An acid such as a boronic acid, such as phenylboronic acid, is used to protect the 2 ′ and 3 ′ hydroxyl groups on the sugar residue. Coupling the SATE intermediate with a nucleoside phenylboronate derivative can provide good yields, and phenylboronate deprotection can be conveniently performed with an acid such as aqueous citric acid during workup of the reaction mixture. Cleaning is performed. Final removal of protecting groups such as trityl groups (relative to the Sate moiety) is done gently by using an organic solvent system such as an acetyl chloride / ethanol mixture. This deprotection reaction is consistently reproducible, measurable, and can give significantly higher yields.

手順A：
合成スキーム：

2'-C-メチルグアノシン（NM 108）（3g、10.10mmol）、及び化合物5[5の合成については、実施例2を参照されたい］（6.48g、11.10mmol）をピリジン無水物と共に同時蒸発させて、この溶媒（152mL）に溶解した。塩化ピバロイル（2.48mL、20.18mmol）を-15℃にて滴状に添加して、溶液を同じ温度にて2時間撹拌した。反応混合物を塩化メチレンで希釈して、塩化アンモニウム（0.5M NH₄Cl）の水溶液で中和した。0.5M塩化メチレン／NH₄Cl水溶液で抽出後、有機相を合わせて、Na₂SO₄上で乾燥させて、減圧下で蒸発させ（30℃を上回らない浴温）、トルエンと共に2回同時蒸発させた。粗製混合物をシリカゲルフラッシュカラムクロマトグラフィーで精製し（溶出剤：塩化メチレン中の[0-10%］のメタノール+0.2%酢酸の段階勾配）、所望の生成物6（2.5g、32%）を得た。R_f = 0.30（CH₂Cl₂中の15% MeOH）;

(Example 3)
Preparation of hydroxy-tBuSATE N-benzyl phosphoramidate derivative of B299, 2'-C-methylguanosine

Step A:
Synthesis scheme:

2′-C-methylguanosine (NM 108) (3 g, 10.10 mmol) and compound 5 [See Example 2 for synthesis of 5] (6.48 g, 11.10 mmol) coevaporated with pyridine anhydride And dissolved in this solvent (152 mL). Pivaloyl chloride (2.48 mL, 20.18 mmol) was added dropwise at −15 ° C. and the solution was stirred at the same temperature for 2 hours. The reaction mixture was diluted with methylene chloride and neutralized with an aqueous solution of ammonium chloride (0.5M NH ₄ Cl). After extraction with 0.5M methylene chloride / NH ₄ Cl aqueous solution, the organic phases are combined, dried over Na ₂ SO ₄ , evaporated under reduced pressure (bath temperature not exceeding 30 ° C.) and co-evaporated twice with toluene. I let you. The crude mixture is purified by flash column chromatography on silica gel (eluent: [0-10%] methanol in methylene chloride + 0.2% acetic acid step gradient) to give the desired product 6 (2.5 g, 32%). It was. R _f = 0.30 (15% MeOH in CH ₂ Cl ₂ );

To a solution of compound 6 (2.5 g, 3.27 mmol) in carbon tetrachloride anhydride (33 mL) was added benzylamine (5 eq, 1.79 mL) dropwise. The reaction mixture was stirred at room temperature for 1 h and evaporated under reduced pressure (bath temperature not exceeding 30 ° C.). The crude mixture was purified by silica gel flash column chromatography (eluent: step gradient of [0-10%] methanol in methylene chloride) to give compound 7 as a white foam (2.9 g, quantitative yield). R _f = 0.27 (10% MeOH in CH ₂ Cl ₂ );

Compound 7 (2.84 g, 3.27 mmol) was dissolved in a mixture of trifluoroacetic acid (1.1 mL) and methylene chloride (11.4 mL). The reaction mixture was stirred at room temperature for 0.5 hour. The solution was diluted with ethanol and evaporated under reduced pressure (bath temperature not exceeding 3O 0 C) and co-evaporated twice with toluene. The crude mixture was purified by silica gel flash column chromatography (eluent: [0-30%] methanol step gradient in methylene chloride) and then by reverse phase column chromatography (eluent: [0- Step gradient), the desired product 8 (B299) (1: 1 mixture of diastereoisomers according to ³¹ P-NMR, 800 mg, 39%) was obtained, which was a mixture of dioxane / water. And lyophilized. R _f = 0.57 (20% MeOH in CH ₂ Cl ₂ );

合成スキーム：

2'-C-メチルチミジン（NM105）（700mg、2.57mmol）、及び5[5の合成については、実施例2を参照されたい］（1.1eq、1.6g）をピリジン無水物と共に同時蒸発させて、この溶媒（40mL）に溶解した。塩化ピバロイル（2.0eq、0.633mL）を-15℃にて滴状に添加し、溶液をこの温度にて1時間30分間撹拌した。反応混合物を塩化メチレンで希釈して、塩化アンモニウム（0.5M NH₄Cl）の水溶液で中和した。0.5M塩化メチレン／水溶液NH₄Clで抽出後、有機相を合わせて、減圧下で蒸発させて（30℃を上回らない浴温）、トルエンと共に同時蒸発させた。粗製混合物をシリカゲルカラムクロマトグラフィーで精製し（溶出剤：塩化メチレン中の[0-10%］のメタノール+ 0.2%酢酸の段階勾配）、所望の生成物6を得て、これをトルエンと共に同時蒸発させて白い泡（942mg、50%）を得た。R_f= 0.56（CH₂Cl₂中の15% MeOH）；

(Example 4)
Preparation of hydroxy-tBuSATE N-benzyl phosphoramidate derivatives of 2'-C-methylthymidine

Synthesis scheme:

2′-C-methylthymidine (NM105) (700 mg, 2.57 mmol), and 5 [See Example 2 for the synthesis of 5] (1.1 eq, 1.6 g) co-evaporated with pyridine anhydride , Dissolved in this solvent (40 mL). Pivaloyl chloride (2.0 eq, 0.633 mL) was added dropwise at -15 ° C. and the solution was stirred at this temperature for 1 hour 30 minutes. The reaction mixture was diluted with methylene chloride and neutralized with an aqueous solution of ammonium chloride (0.5M NH ₄ Cl). After extraction with 0.5M methylene chloride / water solution NH ₄ Cl, the organic phases were combined, evaporated under reduced pressure (bath temperature not exceeding 30 ° C.) and co-evaporated with toluene. The crude mixture is purified by silica gel column chromatography (eluent: [0-10%] methanol in methylene chloride + 0.2% acetic acid step gradient) to give the desired product 6, which is co-evaporated with toluene. To give a white foam (942 mg, 50%). R _f = 0.56 (15% MeOH in CH ₂ Cl ₂ );

To a solution of compound 6 (920 mg, 1.25 mmol) in carbon tetrachloride anhydride (13 mL) was added benzylamine (10 eq, 1.4 mL) dropwise. The reaction mixture was stirred at room temperature for 2 hours. A white precipitate appeared. The solution was diluted with methylene chloride and neutralized with an aqueous solution of hydrogen chloride (HCl 1M). After sequential extraction with CH ₂ Cl ₂ / HCl IM and CH ₂ Cl ₂ / NaHCO ₃ aqueous solution, the organic phases were combined, dried over Na ₂ SO ₄ , filtered and evaporated to dryness. The crude mixture was purified by column chromatography on silica gel (eluent: [0-10%] methanol step gradient in methylene chloride) to give 7 as a white foam (875 mg, 83%). R _f = 0.56 (15% MeOH in CH ₂ Cl ₂ );

Finally, compound 7 (860 mg, 1.02 mmol) was dissolved in a mixture of methylene chloride (15 mL) and trifluoroacetic acid (0.51 mL). The reaction mixture was stirred at room temperature for 2 hours and then diluted with toluene. Volatiles were evaporated under reduced pressure and co-evaporated with ethanol. The crude mixture was purified by silica gel column chromatography (eluent: [0-10%] step gradient of methanol in methylene chloride) followed by purification by reverse phase chromatography (eluent: [0- 50%] acetonitrile step gradient) to give the desired product 8 (B208) (257 mg, 42%). R _f = 0.31 (10% MeOH in CH ₂ Cl ₂ );

手順A：
中間体4の合成：

濃縮器を装着した500mLの3首フラスコに、PMEA（2.00g、7.25mmol）、CH₂Cl₂（121mL）、及びDMF（617μL、7.98mmol）を充填した。生じるスラリーを勢いよく撹拌して、塩化オキサリル（2.21mL、25.4mmol）を0℃にて10分（気体発生）にわたって滴状に添加した。スラリーが黄色溶液（10分）に変わった後、濁った（10分）。これを還流下で更に3時間撹拌すると、白く、濃いスラリーに変わった。減圧下で室温にて全ての揮発性物質を蒸発することによって、生成物をその場で1時間、シュレンク（schlenk）乾燥させた。次いで、生じる黄色の固体をCH₂Cl₂（121mL）に部分的に溶解させて、ピリジン（1.17mL、14.5mmol）をO℃にて10分にわたって滴状に添加した。白い懸濁液が青色溶液に変わり、これを-78℃に冷却した。次いで、アルコール3[3の合成については、実施例1を参照されたい］（3.480g、7.25mmol）、及びCH₂Cl₂（72mL）中のトリエチルアミン（6.37mL、45.7mmol）の溶液を滴状に内部壁に沿ってゆっくりと添加し（およそ45分）、反応を-78℃にて10時間撹拌した。次いで、ベンジルアミン（2.37mL、21.7mmol）を-78℃にて滴状に添加して、溶液を撹拌したまま1時間にわたって室温に加温した。NaHCO₃（飽和水溶液、200mL）を反応の上に注いで、層を分離した。水相をCH₂Cl₂（2×100mL）で抽出して、合わせた有機抽出物を鹹水（50mL）、及びNa₂SO₄で乾燥させた。溶液を濾過して、濃縮し、およそ6.5gの粗製黄色シロップを得た。CH₂Cl₂（1% Et₃N）中の4→8→12% MeOHで溶出するフラッシュカラムクロマトグラフィー（SiO₂、φ= 3.5cm、H =11cm）によって精製し、3.70gの黄色の泡（0.15＜Rf＜0.30、CH₂Cl₂中の10% MeOH）のを得て、これをCH₂Cl₂（1% Et₃N）中の4→6% MeOHで溶出するフラッシュカラムクロマトグラフィー（SiO₂、φ= 3.5cm、H=12cm）によって第2の精製に供して、3.70gの黄色の泡（0.15＜Rf＜0.30、CH₂Cl₂中の10% MeOH）を得た。これをCH₂Cl₂（1% Et₃N）中の4→6% MeOHで溶出するフラッシュカラムクロマトグラフィー（SiO₂、φ= 3.5cm、H =12cm）による3回目の精製に供して、白い泡として165mgのホスホンアミダート4（およそ2.7%）、及び1.75gの混合化合物を生成した。これらをCH₂Cl₂（1% Et₃N）中の4→6% MeOHで溶出するフラッシュカラムクロマトグラフィー（SiO₂、φ= 3.5cm、H =12cm）による最後の精製に供し、353mgの白い泡としてホスホンアミダート4（およそ5.9%）を得た。全収率：8.6%。 R_f= 0.21（CH₂Cl₂中の6% MeOH）；

(Example 5)
Preparation of B261 (hydroxy-tBuSATE N-benzylphosphonoamidade derivative of PMEA

Step A:
Synthesis of Intermediate 4:

A 500 mL 3-necked flask equipped with a concentrator was charged with PMEA (2.00 g, 7.25 mmol), CH ₂ Cl ₂ (121 mL), and DMF (617 μL, 7.98 mmol). The resulting slurry was stirred vigorously and oxalyl chloride (2.21 mL, 25.4 mmol) was added dropwise at 0 ° C. over 10 minutes (gas evolution). The slurry turned cloudy (10 minutes) after turning into a yellow solution (10 minutes). This was stirred at reflux for an additional 3 hours and turned into a white, thick slurry. The product was schlenk dried in situ for 1 hour by evaporating all volatiles at room temperature under reduced pressure. The resulting yellow solid was then partially dissolved in CH ₂ Cl ₂ (121 mL) and pyridine (1.17 mL, 14.5 mmol) was added dropwise at 10 ° C. over 10 minutes. The white suspension turned into a blue solution, which was cooled to -78 ° C. Then a solution of triethylamine (6.37 mL, 45.7 mmol) in CH ₃ Cl ₂ (72 mL) and alcohol 3 [see Example 1 for the synthesis of 3] (3.480 g, 7.25 mmol) and CH ₂ Cl ₂ (72 mL) is then added dropwise. Was slowly added along the inner wall (approximately 45 minutes) and the reaction was stirred at −78 ° C. for 10 hours. Benzylamine (2.37 mL, 21.7 mmol) was then added dropwise at −78 ° C. and the solution was allowed to warm to room temperature over 1 hour with stirring. NaHCO ₃ (saturated aqueous solution, 200 mL) was poured over the reaction and the layers were separated. The aqueous phase was extracted with CH ₂ Cl ₂ (2 × 100 mL) and the combined organic extracts were dried with brine (50 mL) and Na ₂ SO ₄ . The solution was filtered and concentrated to give approximately 6.5 g of a crude yellow syrup. Purified by flash column chromatography (SiO ₂ , φ = 3.5 cm, H = 11 cm) eluting with 4 → 8 → 12% MeOH in CH ₂ Cl ₂ (1% Et ₃ N), 3.70 g of yellow foam to give (0.15 <Rf <0.30, CH 2 10% MeOH in Cl ₂₎ to which a flash column chromatography eluting with _{CH 2 Cl 2 (1% Et} 3 N) in the 4 → 6% MeOH ( A _second purification with SiO ₂ , φ = 3.5 cm, H = 12 cm) gave 3.70 g of yellow foam (0.15 <Rf <0.30, 10% MeOH in CH ₂ Cl ₂ ). This was subjected to a third purification by flash column chromatography (SiO ₂ , φ = 3.5 cm, H = 12 cm) eluting with 4 → 6% MeOH in CH ₂ Cl ₂ (1% Et ₃ N), white 165 mg of phosphonamidate 4 (approximately 2.7%) and 1.75 g of mixed compound were produced as foam. These were subjected to final purification by flash column chromatography (SiO ₂ , φ = 3.5 cm, H = 12 cm) eluting with 4 → 6% MeOH in CH ₂ Cl ₂ (1% Et ₃ N) and 353 mg white Phosphonamidate 4 (approximately 5.9%) was obtained as a foam. Overall yield: 8.6%. R _f = 0.21 (6% MeOH in CH ₂ Cl ₂ );

ジクロロ酢酸（CH₂Cl₂（およそ140滴）中の20% 溶液）を0℃にてCH₂Cl₂（4.3mL）中のエーテル4（353mg、0.43mmol）の溶液に滴下して、これを55分間撹拌した。次いで、固体のNaHCO₃（およそ1.5g）を添加して、スラリーを10分間撹拌した後、濾過、及び蒸発させた。
CH₂Cl₂中の4% →10% MeOHで溶出するフラッシュカラムクロマトグラフィー（SiO₂、φ= 1.5cm、H =10cm）によって精製し、純粋なホスホンアミダート5を得た（THF/H₂O中の凍結乾燥、及びP₂O₅デシケータ（58%）中の3日置いた後、130mg）。また、この反応を165mgのエーテル4にも実施し、51mgのホスホンアミダート5（B261、49%）を得た。R_f= 0.20（CH₂Cl₂中の10% MeOH）；

Synthesis of Compound 5 (B261):

Dichloroacetic acid (20% solution in CH ₂ Cl ₂ (approximately 140 drops)) was added dropwise at 0 ° C. to a solution of ether 4 (353 mg, 0.43 mmol) in CH ₂ Cl ₂ (4.3 mL). Stir for 55 minutes. Solid NaHCO ₃ (approximately 1.5 g) was then added and the slurry was stirred for 10 minutes before being filtered and evaporated.
Purification by flash column chromatography (SiO ₂ , φ = 1.5 cm, H = 10 cm) eluting with 4% → 10% MeOH in CH ₂ Cl ₂ to give pure phosphonamidate 5 (THF / H ₂ 130 mg) after lyophilization in O and 3 days in P ₂ O ₅ desiccator (58%). This reaction was also performed on 165 mg ether 4 to give 51 mg phosphonamidate 5 (B261, 49%). R _f = 0.20 (10% MeOH in CH ₂ Cl ₂ );

工程1：中間体Aの合成
120mLのDCM（無水物）中のPMEA（2g、7.3mmol）の懸濁液に、DMF（640mg、1.2eq）、続いて塩化オキサリル（2.3mL、3.5eq）を室温で添加した。混合物を1.5時間還流まで加熱し、濃い黄色の懸濁液を得た。混合物をロータベープ（rotarvap）により乾燥まで濃縮し、淡黄色の固体として粗製中間体2を得た。メタノール性溶液中の中間体2の一定分量のLCMS解析により、優れた純度の生成物の構造を確認した。 Step B:
[Improved Preparation of PMEA Hydroxy-tBuSATE N-Benzyl Phosphoramidate Derivative (B261, Compound 5)]
Synthesis scheme:

Step 1: Synthesis of Intermediate A
To a suspension of PMEA (2 g, 7.3 mmol) in 120 mL DCM (anhydrous) was added DMF (640 mg, 1.2 eq) followed by oxalyl chloride (2.3 mL, 3.5 eq) at room temperature. The mixture was heated to reflux for 1.5 hours to give a dark yellow suspension. The mixture was concentrated to dryness by rotarvap to give crude intermediate 2 as a pale yellow solid. An LCMS analysis of an aliquot of Intermediate 2 in methanolic solution confirmed the structure of the product with excellent purity.

Step 2: Synthesis of Intermediate B:
Crude intermediate A (7.33 mmol) was suspended in 100 mL of anhydrous DCM. The suspension was cooled to 0 ° C. To this was added pyridine (1.2 mL, 14.6 mmol, 2 eq) at 0 ° C. After the addition, the pale yellow suspension turned into a golden colored clear solution. The solution was cooled to −32 ° C. with an ACN / dry ice bath. To this was added dropwise solution 3 (3.52 g, 7.33 mmol, 1 eq) in 70 mL DCM anhydrous containing triethylamine (6.3 mL, 44 mmol, 6 eq). The internal reaction temperature was maintained between -35 ° C and -30 ° C during the addition. The light golden colored solution turned into a green colored solution during the addition and some precipitate appeared from the solution. The precipitate was probably triethylamine HCl salt. It took 20 minutes to complete the addition. After the addition, the mixture was stirred at −30 ° C. to −10 ° C. for 1 hour. The reaction mixture was cooled back to -20 ° C. Benzylamine (2.4 mL, 22 mmol, 3 eq) was added. The mixture was stirred at −20 ° C. for 10 minutes. Saturated NaHCO ₃ / H ₂ O was added to the reaction mixture and the mixture was stirred for 2 minutes. The DCM layer was separated, dried over Na ₂ SO ₄ and concentrated to dryness to give crude intermediate B as a yellow viscous oil. HPLC analysis of the crude intermediate showed 62% purity at 272 nm.

Step 3: Synthesis of Intermediate 4:
Crude intermediate B (7.33 mmol) as a viscous light yellow oil was dissolved in 200 mL of MeOH. The reaction mixture was refluxed overnight. HPLC analysis of the reaction mixture showed complete conversion of amidine to amine. [Retention time of amidine (RT = 5.92 min) is very close to amine (RT = 5.98 min) in the current tissue HPLC method! ]. The mixture was cooled to RT and filtered. The filtrate was concentrated to dryness by rotavapor. The resulting crude product was purified by silica gel column chromatography (using 3-8% MeOH in DCM, 12Og silica gel combiflash column as eluent) in 51% isolated yield from 2 g PMEA. 3.1 g of pure product was obtained as a white foam. The resulting 1H-NMR of 4 was consistent with the desired structure. HPLC analysis of the resulting 4 showed 96% purity (AUC).

Step 4: Synthesis of B261 (Compound 5) Intermediate 4 (300 mg, 0.36 mmol) was dissolved in EtOH (anhydrous, 5 mL). To this was added 1 part of acetyl chloride (43 mg, 1.5 eq) at room temperature. The reaction should be operated in a closed reaction flask to avoid loss of HCl gas. The reaction mixture was stirred for 30 min at RT. To this was added solid NaHCO ₃ and the mixture was stirred for 15 minutes. The pH of the reaction mixture was found to be 7-8. The mixture was filtered and the filtrate was concentrated to dryness. The crude product was purified by silica gel column chromatography (5-10% MeOH in DCM as eluent) to give 163 mg of 5 as a clear viscous oil in 86% yield. The 1H-NMR of the product obtained was consistent with the desired structure. HPLC analysis of the resulting product showed 97.4% purity (AUC).

合成スキーム：

プロヌクレオチドB263（94mg、6% 全収率）は、実施例2（手順A、ストラテジーb）において調製したプロヌクレオチドの合成のために記述したものと同様の手順に従って、その親ヌクレオシドの2'-C-メチル-6-NH-ジメトキシトリチル-アデノシン（1.59g、2.73mmol）から合成され、白い凍結乾燥粉末として単離された。

(Example 6)
Preparation of hydroxy-tBuSATE N-benzyl phosphoramidate derivative of B263,2'-C-methyladenosine

Synthesis scheme:

Pronucleotide B263 (94 mg, 6% overall yield) was obtained according to a procedure similar to that described for the synthesis of the pronucleotide prepared in Example 2 (Procedure A, Strategy b). Synthesized from C-methyl-6-NH-dimethoxytrityl-adenosine (1.59 g, 2.73 mmol) and isolated as a white lyophilized powder.

プロヌクレオチド6（446mg、0.76mmol、4工程にわたって全収率9%）は、実施例2（ストラテジーA. B229 6）において調製したプロヌクレオチドの合成のために記述したのと同様の手順に従って、そのヌクレオシド親1から合成した。 (Example 7)
Preparation of hydroxy-tBuSATE N-benzyl phosphoramidate derivatives of B229, 2'-C-methyluridine

Pronucleotide 6 (446 mg, 0.76 mmol, 9% overall yield over 4 steps) was obtained according to a procedure similar to that described for the synthesis of pronucleotide prepared in Example 2 (Strategy A. B229 6). Synthesized from nucleoside parent 1.

合成スキーム：

プロヌクレオチドB186（314mg、8% 全収率）は、実施例2（手順A、ストラテジーa）において調製したプロヌクレオチドの合成のために記述したものと同様の手順の後に、その親ヌクレオシド2',3'-O-イソプロピリデン-2'-C-メチル-イノシン（2.0g、6.26mmol）から合成され、白い凍結乾燥粉末として単離された。

(Example 8)
Preparation of hydroxy-tBuSATE N-benzyl phosphoramidate derivative of B186, 2'-C-methylinosine

Synthesis scheme:

Pronucleotide B186 (314 mg, 8% overall yield) is obtained after a procedure similar to that described for the synthesis of the pronucleotide prepared in Example 2 (Procedure A, Strategy a) after its parent nucleoside 2 ′, Synthesized from 3′-O-isopropylidene-2′-C-methyl-inosine (2.0 g, 6.26 mmol) and isolated as a white lyophilized powder.

合成スキーム：

プロヌクレオチドB396（75mg、10% 全収率）は、実施例4において調製したプロヌクレオチドの合成のために記述したものと同様の手順の後に、その親ヌクレオシド9-[2-C-メチル-β-リボフラノシル］-6-クロロプリン（571mg、1.90mmol）から合成され、白い凍結乾燥粉末として単離された。

(Example 9)
Preparation of hydroxy-tBuSATE N-benzyl phosphoramidate derivative of B396, 9- [2-C-methyl-β-ribofuranosyl] -6-chloropurine

Synthesis scheme:

Pronucleotide B396 (75 mg, 10% overall yield) was obtained after a procedure similar to that described for the synthesis of the pronucleotide prepared in Example 4 after its parent nucleoside 9- [2-C-methyl-β -Ribofuranosyl] -6-chloropurine (571 mg, 1.90 mmol) and was isolated as a white lyophilized powder.

合成スキーム：

N-ベンジルアミニル-2',3'-O-カルボナート-2'-C-メチルグアノシン-5'-イル-O-(トリフェニルメチルオキシ-tert-ブチル-S-アシル-2-チオエチル）ホスフェート（C1）：
化合物B2[化合物7、実施例3、手順Aを参照されたい。］（250mg、0.288mmol）をジメチルホルムアミド（3.5mL）に溶解して、1,1-カルボニルジイミダゾール（186.60mg、1.15mmol）で処理した。混合物を室温で4時間30分間撹拌して、減圧下で濃縮した（30℃を上回らない浴温）。粗製残渣をシリカゲルクロマトグラフィーに供して、ジクロロメタン中の0〜10% メタノール勾配で溶出させ、無色油状物としてC1を得た。（68mg、26%）。化合物C1：

(Example 10)
Preparation of hydroxy-tBuSATE N-benzyl phosphoramidate derivative of B307, 2 ', 3'-O-carbonate-2'-C-methylguanosine

Synthesis scheme:

N-Benzylaminol-2 ', 3'-O-carbonate-2'-C-methylguanosine-5'-yl-O- (triphenylmethyloxy-tert-butyl-S-acyl-2-thioethyl) phosphate (C1):
Compound B2 [compound 7, see example 3, procedure A. ] (250 mg, 0.288 mmol) was dissolved in dimethylformamide (3.5 mL) and treated with 1,1-carbonyldiimidazole (186.60 mg, 1.15 mmol). The mixture was stirred at room temperature for 4 hours 30 minutes and concentrated under reduced pressure (bath temperature not exceeding 30 ° C.). The crude residue was subjected to silica gel chromatography, eluting with a 0-10% methanol gradient in dichloromethane to give C1 as a colorless oil. (68 mg, 26%). Compound C1:

N-benzylaminyl-O- (hydroxy-tert-butyl-S-acyl-2-thioethyl) -2 ', 3'-O-carbonate-2'-C-meth-ylguanosine-5'-yl phosphate B307 (Compound C2):
Compound C1 (65 mg, 0.073 mmol) was dissolved in dichloromethane (260 μL) and treated with TFA (26 μL). The mixture was stirred at room temperature for 15 minutes, then diluted with ethanol, evaporated to dryness (bath temperature not exceeding 30 ° C.) and coevaporated with toluene. The resulting residue was purified by reverse phase (C 18) silica gel column chromatography eluting with a 0-100% acetonitrile gradient in water, lyophilized from a water / dioxane mixture, and B307 (compound C2) (34 mg, 72% White lyophilized powder). B307 (Compound C2):

合成スキーム

2'-C-メチルグアノシン-5'-イル-N-(4-トリフルオロメチル)-ベンジルアミニル-O-(トリフェニルメチルオキシ-tert-ブチル-S-アシル-2-チオエチル）ホスフェート（D1）：
四塩化炭素無水物中の化合物B1[化合物7、実施例3、手順Aを参照されたい。］（355mg、0.465mmol）の溶液に、（4.65mL）4-トリフルオロメチルベンジルアミン（331μL、2.324mmol）を添加した。反応混合物を室温で1時間30分間撹拌して、減圧下で濃縮した（30℃を上回らない浴温）。生じる残渣をシリカゲルクロマトグラフィーに供して、ジクロロメタン中の0〜10% メタノール勾配で溶出し、白色固体としてD1を得た。（420mg、96%）。化合物D1：

(Example 11)
Preparation of hydroxy-tBuSATE N- (4-trifluoromethyl) benzyl phosphoramidate derivative of B242, 2'-C-methylguanosine:

Synthesis scheme

2'-C-methylguanosine-5'-yl-N- (4-trifluoromethyl) -benzylaminyl-O- (triphenylmethyloxy-tert-butyl-S-acyl-2-thioethyl) phosphate (D1 ):
Compound B1 in carbon tetrachloride anhydride [see Compound 7, Example 3, Procedure A. ] (355 mg, 0.465 mmol) was added (4.65 mL) 4-trifluoromethylbenzylamine (331 μL, 2.324 mmol). The reaction mixture was stirred at room temperature for 1 h 30 and concentrated under reduced pressure (bath temperature not exceeding 30 ° C.). The resulting residue was subjected to silica gel chromatography, eluting with a gradient of 0-10% methanol in dichloromethane to give D1 as a white solid. (420 mg, 96%). Compound D1:

O- (Hydroxy-tert-butyl-S-acyl-2-thioethyl) -2'-C-methylguanosine-5'-yl-N- (4-trifluoromethyl) -benzylaminyl phosphate B242 (Compound D2) :
Compound D1 (400 mg, 0.427 mmol) was dissolved in dichloromethane (1.6 mL) and treated with TFA (160 μL). The mixture was stirred at room temperature for 15 minutes, then diluted with ethanol, evaporated to dryness (bath temperature not exceeding 30 ° C.) and coevaporated with toluene. The resulting residue is subjected to silica gel chromatography and purified by reverse phase (C 18) silica gel column chromatography eluting with a gradient of 0-15% methanol in dichloromethane and then with a gradient of 0-100% acetonitrile in water. And lyophilized from a water / dioxane mixture to give Compound B2742 (Compound D2) (90 mg, 30%, white lyophilized powder). B242 (Compound D2):

合成スキーム：

｛9-[(2R)2-デオキシ-2-フルオロ-2-C-エチニル-β-D-エリスロ-フラノシル]-グアニン｝-5'-イル-O-(トリフェニルメチルオキシ-tert-ブチル-S-アシル-2-チオエチル）H-ホスホナート（G1）：
化合物B5[未発表の結果］（100mg、0.32mmol）、及び化合物F3[実施例2の化合物5を参照されたい］（246mg、0.42mmol）をピリジン無水物と共に同時蒸発させて、この溶媒（4.8mL）に溶解した。塩化ピバロイル（80μL、0.64mmol）を-15℃にて滴状に添加し、溶液を同じ温度にて2時間撹拌した。反応混合物をジクロロメタンで希釈して、0.5M、NH₄Clの水溶液で中和した。混合物をジクロロメタンと0.5M、NH₄Cl水溶液との間で分けて、有機相を合わせて、Na₂SO₄上で乾燥させて、減圧下で蒸発させ（30℃を上回らない浴温）、トルエンで2回同時蒸発させた。粗製混合物をジクロロメタン中の0-10% メタノール勾配+ 0.2% 酢酸で溶出するフラッシュカラムクロマトグラフィーによって精製した、無色油状物（68mg、28%）として所望の生成物G1を得た。化合物G1：

(Example 12)
Preparation of hydroxy-tBuSATE N-benzyl phosphoramidate derivative of B503,9-[(2R) 2-deoxy-2-fluoro-2-C-ethynyl-β-D-erythro-furanosyl] -guanine

Synthesis scheme:

{9-[(2R) 2-deoxy-2-fluoro-2-C-ethynyl-β-D-erythro-furanosyl] -guanine} -5'-yl-O- (triphenylmethyloxy-tert-butyl- S-acyl-2-thioethyl) H-phosphonate (G1):
Compound B5 [unpublished results] (100 mg, 0.32 mmol) and compound F3 [see compound 5 of Example 2] (246 mg, 0.42 mmol) were co-evaporated with pyridine anhydride to give this solvent (4.8 mL). Pivaloyl chloride (80 μL, 0.64 mmol) was added dropwise at −15 ° C. and the solution was stirred at the same temperature for 2 hours. The reaction mixture was diluted with dichloromethane and neutralized with an aqueous solution of 0.5M NH ₄ Cl. The mixture was partitioned between dichloromethane and 0.5M, aqueous NH ₄ Cl, the organic phases combined, dried over Na ₂ SO ₄ and evaporated under reduced pressure (bath temperature not exceeding 30 ° C.) toluene And co-evaporated twice. The crude mixture was purified by flash column chromatography eluting with a 0-10% methanol gradient in dichloromethane + 0.2% acetic acid to give the desired product G1 as a colorless oil (68 mg, 28%). Compound G1:

  N-benzylaminyl- {9-[(2R) 2-deoxy-2-fluoro-2-C-ethynyl-β-D-erythro-furanosyl] -guanine} -5'-yl-O- (triphenylmethyl Oxy-tert-butyl-S-acyl-2-thioethyl) phosphate (G2)

To a solution of compound G1 (68 mg, 0.088 mmol) in carbon tetrachloride anhydride (880 μL) was added benzylamine (48 μL, 0.44 mmol) dropwise. The reaction mixture was stirred at room temperature for 2 hours and evaporated to dryness (bath temperature not exceeding 30 ° C.). The crude mixture was filtered through a silica gel plug eluting with a gradient 0-10% methanol in dichloromethane to give compound G2 as a white solid (80 mg, quantitative yield). Compound G2:

N-benzylaminyl- {9-[(2R) 2-deoxy-2-fluoro-2-C-ethynyl-β-D-erythro-furanosyl] -guanine} -5'-yl-O- (hydroxy-tert -Butyl-S-acyl-2-thioethyl) phosphate B503 (Compound G3):
Compound G2 (80 mg, 0.09 mmol) was dissolved in dichloromethane (320 μL) and treated with TFA (32 μL). The mixture is stirred at room temperature for 10 minutes, filtered through a solid phase extraction column eluting with a 0-30% methanol gradient in dichloromethane and then reverse phase (C 18) silica gel eluting with a 0-100% acetonitrile gradient in water. Purification by column chromatography and lyophilized from a water / dioxane mixture gave compound B503 (Compound G3) (15 mg, 26%, white lyophilized powder). B503 (Compound G3):

The starting nucleoside was synthesized as follows:
Synthesis of 9-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-furanosyl] -guanine (D961, the starting nucleoside of Example 12) and its triphosphate derivative Synthesis of B427

9-[3,5-O-(1,3-ジイル-1,1,3,3,-テトライソプロピルジシロキサン)-リボ-フラノシル］-N²-イソブチリル-グアニン（B1）：Hirao,I.；Ishikawa, M.；Miura, K. Chem. Lett. 1986、11、1929-1932。
9-[3,5-O-(1,3-ジイル-1,1,3,3-テトライソプロピルジシロキサン)-2-C-トリメチルシリルエチニル-β-D-アラビノ-フラノシル］-N²-イソブチリル-グアニン（B2）：ジクロロメタン（220mL）中のCrO₃（11.07g、110.76mmol）の懸濁液に、O℃にて無水酢酸（10.4mL、110.76mmol）、及びピリジン無水物（17.82mL、221.52mmol）を添加した。ジクロロメタン（110mL）中の溶液中の化合物B1（22g、36.92mmol）を滴状に添加した。冷却浴を除去して、生じる溶液を室温で5時間撹拌した。反応混合物を冷却酢酸エチルに注いで、シリカ、及びセライトゲルプラグを通して濾過して、乾燥まで濃縮して、トルエンで2回同時蒸発させた。得られた残渣をジクロロメタンに溶解して、一晩過剰MgSO₄と共に撹拌して、濾過して、蒸発させ、ケトンを得た。トリメチルシリルアセチレン（12.5mL、88.60mmol）をアルゴン下でTHF無水物（98mL）に溶解した。ブチルリチウム（55.4mL、ヘキサン中の1.6M）を-78℃にて滴状に添加した。反応混合物を-78℃にて30分間撹拌し、次いで-55℃まで暖めた。THF（49mL）中の溶液のケトンを-78℃にて滴状に添加した。反応混合物を-78℃にて1時間撹拌し、次いで-30℃まで暖めて、3時間撹拌した。反応を、-78℃にて飽和NH₄Cl水溶液（72mL）を慎重に添加することによってクエンチした。室温に温めた後、混合物を酢酸エチルで希釈して、飽和かん水で2回洗浄し、乾燥乾燥（Na₂SO₄）させて、乾燥まで濃縮した。粗製物質をジクロロメタン中の1.5% MeOHで溶出するカラムクロマトグラフィーを使用して精製し、淡黄色の泡として化合物B2（8.59g、34%、2工程）を得た。化合物B2：

Synthesis scheme:

9- [3,5-O- (1,3-diyl-1,1,3,3, -tetraisopropyldisiloxane) -ribo-furanosyl] -N ² -isobutyryl-guanine (B1): Hirao, I. Ishikawa, M .; Miura, K. Chem. Lett. 1986, 11, 1929-1932.
9- [3,5-O- (1,3-Diyl-1,1,3,3-tetraisopropyldisiloxane) -2-C-trimethylsilylethynyl-β-D-arabino-furanosyl] -N ² -isobutyryl -Guanine (B2): To a suspension of CrO ₃ (11.07 g, 110.76 mmol) in dichloromethane (220 mL), acetic anhydride (10.4 mL, 110.76 mmol) and pyridine anhydride (17.82 mL, 221.52) at O ° C. mmol) was added. Compound B1 (22 g, 36.92 mmol) in solution in dichloromethane (110 mL) was added dropwise. The cooling bath was removed and the resulting solution was stirred at room temperature for 5 hours. The reaction mixture was poured into cold ethyl acetate, filtered through a silica and celite gel plug, concentrated to dryness and coevaporated twice with toluene. The resulting residue was dissolved in dichloromethane and stirred with excess MgSO ₄ overnight, filtered and evaporated to give the ketone. Trimethylsilylacetylene (12.5 mL, 88.60 mmol) was dissolved in anhydrous THF (98 mL) under argon. Butyllithium (55.4 mL, 1.6 M in hexane) was added dropwise at -78 ° C. The reaction mixture was stirred at -78 ° C for 30 minutes and then warmed to -55 ° C. A solution of ketone in THF (49 mL) was added dropwise at -78 ° C. The reaction mixture was stirred at -78 ° C for 1 hour, then warmed to -30 ° C and stirred for 3 hours. The reaction was quenched at −78 ° C. by careful addition of saturated aqueous NH ₄ Cl (72 mL). After warming to room temperature, the mixture was diluted with ethyl acetate, washed twice with saturated brine, dried (Na ₂ SO ₄ ) and concentrated to dryness. The crude material was purified using column chromatography eluting with 1.5% MeOH in dichloromethane to give compound B2 (8.59 g, 34%, 2 steps) as a pale yellow foam. Compound B2:

9-[(2R) -2-deoxy-2-fluoro-3,5-O (1,3-diyl-1,1,3,3-tetraisopropyldisiloxane) -2-C-trimethyl-silylethynyl- β-D-erythro-furanosyl] -N ² -isobutyryl-guanine (B3):
Compound B2 (2.00 g, 2.89 mmol) was dissolved in dry DCM (60 mL) under argon and pyridine (1.45 mL, 18.06 mmol) was added. The reaction mixture was cooled to −20 ° C. and DAST (4.11 mL, 31.35 mmol) was added dropwise. After the addition was complete, the cooling bath was removed. Stirring was continued for 1 hour 15 minutes, the mixture was dissolved in ethyl acetate, poured into saturated NaHCO ₃ and stirred for 5 minutes. The organic layer was washed with saturated brine, dried (Na ₂ SO ₄ ), concentrated and purified by silica gel chromatography eluting with ethyl acetate in DCM (2%) to give the desired compound B3 ( 1.41 g, 70%). Compound B3:

9-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-furanosyl] -N ² -isobutyryl-guanine (B4):
Compound B3 (1.31 g, 1.89 mmol) was dissolved in methanol (13.8 mL) and ammonium fluoride (908.9 mg, 24.54 mmol) was added. The resulting solution was stirred at reflux for 1 hour and evaporated to dryness. The crude material was purified by silica gel chromatography eluting with a 6-10% methanol step gradient in dichloromethane to give compound B4 (344 mg, 48%) as a pale yellow oil. Compound B4:

9-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-furanosyl] -guanine D961 (compound B5):
Compound B4 (0.78 g, 1.33 mmol) was dissolved in saturated methanolic ammonia (62 mL) and stirred at room temperature for 20 hours. The reaction mixture was then evaporated to dryness under reduced pressure. The residue was dissolved in water and washed twice with ethyl acetate. The aqueous layer was evaporated and purified by reverse phase column chromatography (C18) eluting with a 2-15% acetonitrile gradient in water. The resulting residue was then dissolved in hot ethyl acetate, filtered and dried to give D961 (Compound B5) (134 mg, 33%) as a solid yellow.

ヌクレオシド5'-トリホスフェートの調製のための標準的手順：（Ludwig、J. Acta Biochim. Biophys. Acad. sci. Hung. 1981, 16, 131-133.）
トリエチルホスフェート（750μL）中のヌクレオシド（0.286mmol）の溶液に、塩化ホスホリル（75μL、0.807mmol）を0℃にて添加した。この反応混合物Aを5℃にて一晩撹拌した。トリブチルアンモニウムピロリン酸（PPi/Bu₃N 1/1,5、1g、2.19mmol）をDMF無水物（2mL）に溶解した。トリブチルアミン（420μL、1.76mmol）をPPiに添加して、生じる混合物を0℃にて15分間撹拌した。2.4mLのこの溶液を反応混合物Aに添加した。反応混合物を0℃にて1分間撹拌した。反応をTEAB 1M（pH = 7,5、10mL）で慎重にクエンチし、0℃にて20分撹拌し、次いで水、及び酢酸エチルで希釈した。水相を減圧下で濃縮した。粗製物質を10^-3-1M TEABの勾配で溶出するDEAE-セファデックスクロマトグラフィーに供した。所望の画分を合わせて、減圧下で濃縮して、水／メタノールの混合物と共に同時蒸発させて、最後に水と共に同時蒸発させた。生じる残渣を半分取HPLCで精製した。予想される生成物を含む画分を減圧下で濃縮して、水／メタノールの混合物と共に同時蒸発させ、水から凍結乾燥させた。トリエチルアンモニウム塩トリホスフェートをダウエックスNa⁺樹脂カラムで、水で3回溶出させ、水からナトリウム塩まで凍結乾燥後に得た。 Synthesis scheme:

Standard procedure for the preparation of nucleoside 5'-triphosphates: (Ludwig, J. Acta Biochim. Biophys. Acad. Sci. Hung. 1981, 16, 131-133.)
To a solution of nucleoside (0.286 mmol) in triethyl phosphate (750 μL) phosphoryl chloride (75 μL, 0.807 mmol) was added at 0 ° C. The reaction mixture A was stirred at 5 ° C. overnight. Tributylammonium pyrophosphate (PPi / Bu ₃ N 1 / 1,5, 1 g, 2.19 mmol) was dissolved in DMF anhydride (2 mL). Tributylamine (420 μL, 1.76 mmol) was added to PPi and the resulting mixture was stirred at 0 ° C. for 15 minutes. 2.4 mL of this solution was added to reaction mixture A. The reaction mixture was stirred at 0 ° C. for 1 minute. The reaction was carefully quenched with TEAB 1M (pH = 7,5, 10 mL), stirred at 0 ° C. for 20 minutes, then diluted with water and ethyl acetate. The aqueous phase was concentrated under reduced pressure. The crude material was subjected to DEAE-Sephadex chromatography eluting with a gradient of 10 ^-3 -1M TEAB. The desired fractions were combined, concentrated under reduced pressure, coevaporated with a water / methanol mixture and finally coevaporated with water. The resulting residue was purified by semi-preparative HPLC. Fractions containing the expected product were concentrated under reduced pressure, co-evaporated with a water / methanol mixture and lyophilized from water. Triethylammonium salt triphosphate was eluted 3 times with water on a Dowex Na ⁺ resin column and obtained after lyophilization from water to sodium salt.

9-[(2R) 2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-furanosyl] -guanine 5′-triphosphate sodium salt (B427):

合成スキーム：

プロヌクレオチドB306（25mg、6% 全収率）は、実施例4において調製したプロヌクレオチドの合成のために記述したものと同様の手順の後に、その親ヌクレオシド2'-C-メチル-5-アザ-7-デアザ-グアノシン（200mg、0.67mmol）から合成され、白い凍結乾燥粉末として単離された。

(Example 13)
Preparation of hydroxy-tBuSATE N-benzyl phosphoramidate derivative of B306, 2'-C-methyl-5-aza-7-deaza-guanosine

Synthesis scheme:

Pronucleotide B306 (25 mg, 6% overall yield) was obtained after a procedure similar to that described for the synthesis of the pronucleotide prepared in Example 4 after its parent nucleoside 2′-C-methyl-5-aza. Synthesized from -7-deaza-guanosine (200 mg, 0.67 mmol) and isolated as a white lyophilized powder.

合成スキーム：

プロヌクレオチドB389（80mg、21% 全収率）は、実施例4において調製したプロヌクレオチドの合成のために記述したものと同様の手順の後に、その親ヌクレオシド2'-C-メチル-7-デアザグアノシン（200mg、0.67mmol）から合成され、白い凍結乾燥粉末として単離された。

(Example 14)
Preparation of hydroxy-tBuSATE N-benzyl phosphoramidate derivative of B389, 2'-C-methyl-7-deaza-guanosine

Synthesis scheme:

Pronucleotide B389 (80 mg, 21% overall yield) was obtained following procedures similar to those described for the synthesis of the pronucleotide prepared in Example 4 after its parent nucleoside 2′-C-methyl-7-dea. Synthesized from zaguanosine (200 mg, 0.67 mmol) and isolated as a white lyophilized powder.

合成スキーム：

プロヌクレオチドB288（34mg、3% 全収率）は、実施例4において調製したプロヌクレオチドの合成のために記述したものと同様の手順の後に、その親ヌクレオシド3'-C-メチルウリジン（513mg、1.99mmol）から合成され白い凍結乾燥粉末として単離された。

(Example 15)
Preparation of hydroxy-tBuSATE N-benzyl phosphoramidate derivative of B288, 3'-C-methyluridine

Synthesis scheme:

Pronucleotide B288 (34 mg, 3% overall yield) was obtained after a procedure similar to that described for the synthesis of the pronucleotide prepared in Example 4 after its parent nucleoside 3′-C-methyluridine (513 mg, 1.99 mmol) and isolated as a white lyophilized powder.

合成スキーム：

3'-C-メチルグアノシン-5'-イル-O-(トリフェニルメチルオキシ-tert-ブチル-S-アシル-2-チオエチル）H-ホスホナート（E1）：
3'-C-メチルグアノシン（NM76）（233.7mg、0.79mmol）及び化合物A3［実施例2の化合物 5を参照されたい］（504.9mg、0.87mmol）は、無水ピリジンと共に同時蒸発させ、この溶媒（11.8mL）に溶解した。
塩化ピバロイル（193.7μL、1.57mmol）を-15℃にて滴状に添加して、溶液を同じ温度にて2時間撹拌した。反応混合物をジクロロメタンで希釈して、0.5M、NH₄Clの水溶液で中和した。混合物をジクロロメタンと0.5M、NH₄Cl水溶液との間で分けて、有機相を合わせて、Na₂SO₄上で乾燥して、減圧下で蒸発させ（30℃を上回らない浴温）、トルエンで2回同時蒸発させた。粗製混合物をジクロロメタン中の0〜10 % メタノール勾配+ 0.2% 酢酸で溶出するシリカゲルプラグで濾過して所望の生成物E1（250mg、42%）を得た。化合物E1：

(Example 16)
Preparation of hydroxy-tBuSATE N-benzyl phosphoramidate derivative of B350, 3'-C-methylguanosine

Synthesis scheme:

3′-C-methylguanosine-5′-yl-O- (triphenylmethyloxy-tert-butyl-S-acyl-2-thioethyl) H-phosphonate (E1):
3′-C-methylguanosine (NM76) (233.7 mg, 0.79 mmol) and compound A3 [see compound 5 of Example 2] (504.9 mg, 0.87 mmol) were co-evaporated with anhydrous pyridine and the solvent Dissolved in (11.8 mL).
Pivaloyl chloride (193.7 μL, 1.57 mmol) was added dropwise at −15 ° C. and the solution was stirred at the same temperature for 2 hours. The reaction mixture was diluted with dichloromethane and neutralized with an aqueous solution of 0.5M NH ₄ Cl. The mixture was partitioned between dichloromethane and 0.5M, NH ₄ Cl aqueous solution, the organic phases combined, dried over Na ₂ SO ₄ , evaporated under reduced pressure (bath temperature not exceeding 30 ° C.), toluene And co-evaporated twice. The crude mixture was filtered through a silica gel plug eluting with 0-10% methanol gradient in dichloromethane + 0.2% acetic acid to give the desired product E1 (250 mg, 42%). Compound E1:

N-benzylaminyl-3′-C-methylguanosine-5′-yl-O- (triphenylmethyloxy-tert-butyl-S-acyl-2-thioethyl) phosphate (E2):
To a solution of compound E1 (250 mg, 0.33 mmol) in carbon tetrachloride anhydride (3.3 mL) was added benzylamine (178 μL, 1.637 mmol) dropwise. The reaction mixture was stirred at room temperature for 1 hour 30 minutes and evaporated to dryness (bath temperature not exceeding 30 ° C.). The crude mixture was filtered through a silica gel plug eluting with a 0-30% methanol gradient in dichloromethane to give E2 as a white solid (290 mg, quantitative yield). Compound E2:

N-benzylaminyl-O- (hydroxyl-tert-butyl-S-acyl-2-thioethyl) -3′-C-methylguanosine-5′-yl phosphate B350 (compound E3):
Compound E2 (290 mg, 0.33 mmol) was dissolved in dichloromethane (1.16 mL) and treated with TFA (113 μL). The mixture was stirred for 10 minutes at room temperature, then diluted with ethanol, evaporated to dryness (bath temperature not exceeding 30 ° C.) and coevaporated with toluene. The resulting residue is subjected to silica gel chromatography, eluting with a gradient of 0-30% methanol in dichloromethane and then purified by reverse phase (C18) silica gel column chromatography eluting with a gradient of 0-100% acetonitrile in water. Lyophilized from the / dioxane mixture to give B350 (Compound E3) (15 mg, 7%, white lyophilized powder). B350 (Compound E3):

合成スキーム：

プロヌクレオチドB305（28.3mg、8% 全収率）は、実施例4において調製したプロヌクレオチドの合成のために記述したものと同様の手順の後に、その親ヌクレオシド1-[2-C-メチル-β-リボフラノシル]-ピラゾロ-3-カルボキサミド-4-フルオロ（180mg、0.65mmol）から合成され、白い凍結乾燥粉末として単離された。

(Example 17)
Preparation of hydroxy-tBuSATE N-benzyl phosphoramidate derivative of B305, 1- [2-C-methyl-β-ribofuranosyl] -3-carboxamido-4-fluoro-pyrazole

Synthesis scheme:

Pronucleotide B305 (28.3 mg, 8% overall yield) was obtained after a procedure similar to that described for the synthesis of the pronucleotide prepared in Example 4 after its parent nucleoside 1- [2-C-methyl- Synthesized from β-ribofuranosyl] -pyrazolo-3-carboxamido-4-fluoro (180 mg, 0.65 mmol) and isolated as a white lyophilized powder.

合成スキーム：

プロヌクレオチドB436（30mg、9% 全収率）は、実施例2（手順A、ストラテジーb）において調製したプロヌクレオチドの合成ために記述したものと同様の手順の後に、2'-C-メチル-7-デアザ-6-NH-ジメトキシトリチル-アデノシン（320mg、0.53mmol）をその親ヌクレオシドから合成され、白い凍結乾燥粉末として単離された。

(Example 18)
Preparation of hydroxy-tBuSATE N-benzyl phosphoramidate derivative of B436, 2'-C-methyl-7-deaza-7-fluoro-adenosine

Synthesis scheme:

Pronucleotide B436 (30 mg, 9% overall yield) was obtained following procedures similar to those described for the synthesis of the pronucleotide prepared in Example 2 (Procedure A, Strategy b). 7-deaza-6-NH-dimethoxytrityl-adenosine (320 mg, 0.53 mmol) was synthesized from its parent nucleoside and isolated as a white lyophilized powder.

合成スキーム：

実施例4のために記述した手順に従って、かつ4'-C-メチルウリジン（A437）（200mg、0.77mmol）から開始して、中間体P3を最初に生成し（62mg、11%。³¹P NMR（DMSO-d₆、162MHz）δ（ppm）9.15、9.56（2s）；Scan ES⁺ 747（M+Na）⁺、λ_max=259.7nm）、次いで第2の工程の間に化合物P4を（28mg、39%。Scan ES⁺ 852（M+Na）⁺）、及び最後に、所望のプロドラッグB589が、ジオキサン（21mg、58%）からの凍結乾燥後の白色粉末として得られた。

(Example 19)
Preparation of hydroxy-tBuSATE N-benzyl phosphoramidate derivatives of B589, 4'-C-methyluridine

Synthesis scheme:

Following the procedure described for Example 4 and starting with 4′-C-methyluridine (A437) (200 mg, 0.77 mmol), intermediate P3 was initially formed (62 mg, 11%. ³¹ P NMR. (DMSO-d ₆ , 162 MHz) δ (ppm) 9.15, 9.56 (2 s); Scan ES ⁺ 747 (M + Na) ⁺ , λ _max = 259.7 nm), then compound P4 (28 mg during the second step) 39%, Scan ES ⁺ 852 (M + Na) ⁺ ), and finally the desired prodrug B589 was obtained as a white powder after lyophilization from dioxane (21 mg, 58%).

合成スキーム：

実施例3において記述した手順Aの手順に従って、かつ4'-C-フルオロメチルグアノシン（A402）（69.4mg、0.22mmol）から開始して、化合物P1（67.5mg、39%）は、第1の工程後に中間体として得られた。Scan ES-780（M-H）^-。第2の工程により、中間体P2の形成に至った（57.5mg；76%）。化合物P2（26.3mg、0.03mmol）をジクロロメタン（1mL）に溶解して、モンモリロナイトK10（150mg）で処理して、室温で1時間撹拌した。反応混合物を直接シリカSPEチューブ上に沈澱させて、ジクロロメタン中の0〜100 % MeOH勾配で抽出して、白色粉末（7.7mg、40%）としてジオキサン／水B678からの凍結乾燥後に得た。

(Example 20)
Preparation of hydroxy-tBuSATE N-benzyl phosphoramidate derivative of B678, 4'-C-fluoromethylguanosine

Synthesis scheme:

Following the procedure of Procedure A described in Example 3 and starting with 4′-C-fluoromethylguanosine (A402) (69.4 mg, 0.22 mmol), compound P1 (67.5 mg, 39%) Obtained as an intermediate after the process. Scan ES-780 (MH) ^- . The second step led to the formation of intermediate P2 (57.5 mg; 76%). Compound P2 (26.3 mg, 0.03 mmol) was dissolved in dichloromethane (1 mL), treated with montmorillonite K10 (150 mg) and stirred at room temperature for 1 hour. The reaction mixture was precipitated directly on a silica SPE tube and extracted with a 0-100% MeOH gradient in dichloromethane to obtain after lyophilization from dioxane / water B678 as a white powder (7.7 mg, 40%).

合成スキーム：

9-(2-ヒドロキシ-エトキシメチル)-グアニン-5'-イル-O-(トリフェニルメチルオキシ-tert-ブチル-S-アシル-2-チオエチル）H-ホスホナート（F1）；
アシクロビル（200mg、0.89mmol）、及び化合物A3[実施例2の化合物5を参照されたい］（674.2mg、1.15mmol）をピリジン無水物と共に同時蒸発させて、この溶媒（13.3mL）に溶解した。塩化ピバロイル（162μL、1.15mmol）を-15℃にて滴状に添加して、溶液を室温で2時間撹拌した。反応混合物をジクロロメタンで希釈して、0.5M、NH₄Clの水溶液で中和した。混合物をジクロロメタンと0.5M、NH₄Cl水溶液との間で分けて、有機相を合わせて、Na₂SO₄上で乾燥して、減圧下で蒸発させ（30℃を上回らない浴温）、トルエンで2回同時蒸発させた。粗製混合物をジクロロメタン中の0〜15 % メタノール勾配+ 0.2% 酢酸で溶出するシリカゲルプラグで濾過して、所望の生成物F1（602mg、98%）を得た。化合物F1：LR LC/MS (M+H⁺) 691.9 (M-H^-) 690.0 (4.82 min).UV:λ_max= 254 nm.。 (Example 21)
Preparation of hydroxy-tBuSATE N-benzyl phosphoramidate derivative of B704, acyclovir

Synthesis scheme:

9- (2-Hydroxy-ethoxymethyl) -guanine-5′-yl-O- (triphenylmethyloxy-tert-butyl-S-acyl-2-thioethyl) H-phosphonate (F1);
Acyclovir (200 mg, 0.89 mmol) and compound A3 [see compound 5 of Example 2] (674.2 mg, 1.15 mmol) were co-evaporated with pyridine anhydride and dissolved in this solvent (13.3 mL). Pivaloyl chloride (162 μL, 1.15 mmol) was added dropwise at −15 ° C. and the solution was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane and neutralized with an aqueous solution of 0.5M NH ₄ Cl. The mixture was partitioned between dichloromethane and 0.5M, NH ₄ Cl aqueous solution, the organic phases combined, dried over Na ₂ SO ₄ , evaporated under reduced pressure (bath temperature not exceeding 30 ° C.), toluene And co-evaporated twice. The crude mixture was filtered through a silica gel plug eluting with a 0-15% methanol gradient in dichloromethane + 0.2% acetic acid to give the desired product F1 (602 mg, 98%). Compound F1: LR LC / MS (M + H ⁺ ) 691.9 (MH ⁻ ) 690.0 (4.82 min). UV: λ _max = 254 nm.

N-benzylaminyl-9- (2-hydroxy-ethoxymethyl) -guanin-5′-yl-O- (triphenylmethyloxy-tert-butyl-S-acyl-2-thioethyl) phosphate (F2):
To a solution of compound Fl (602 mg, 0.87 mmol) in carbon tetrachloride anhydride (8.7 mL) was added benzylamine (475 μL, 4.35 mmol) dropwise. The reaction mixture was stirred at room temperature for 1 hour 30 minutes and evaporated to dryness (bath temperature not exceeding 30 ° C.). The crude mixture was subjected to silica gel chromatography eluting with a 0-10% methanol gradient in dichloromethane to give compound F2 as a white solid (550 mg, 79%). Compound F2:

N-benzylaminyl-9- (2-hydroxy-ethoxymethyl) -guanin-5′-yl-O- (hydroxy-tert-butyl-S-acyl-2-thioethyl) phosphate B704 (compound F3):
Compound F2 (550 mg, 0.69 mmol) was dissolved in dichloromethane (2.2 mL) and treated with TFA (220 μL). The mixture is stirred for 15 minutes at room temperature, filtered through a solid phase extraction column eluting with a gradient of 0-15% methanol in dichloromethane and then reverse phase (C18) silica gel eluting with a gradient of 0-100% acetonitrile in water. Purification by column chromatography and lyophilized from a water / dioxane mixture gave B704 (Compound F3) (103 mg, 27%, white lyophilized powder). B704 (Compound F3):

合成スキーム：

アセトニトリル無水物中のプロヌクレオチド13（実施例2、手順A、ストラテジーbを参照されたい）（300mg、0.27mmol）の溶液に、トリエチルアミン（92μl）無水酢酸（2.2eq、54μl）、及び4-ジメチルアミノピリジン（0.1eq、4mg）を連続して添加した。反応混合物を室温で2時間撹拌して、トリエチルアミン（92μl）、無水酢酸（2.2eq、54μl）、及び4-ジメチルアミノピリジン（0.1eq、4mg）を再び添加した。減圧下で溶媒を除去後、粗製混合物をシリカゲルカラムクロマトグラフィーで精製し（溶出剤：塩化メチレン中のメタノール[0-5%］の段階勾配）、完全に保護されたプロヌクレオチド（329mg、定量的収率）を得た。最後に、この化合物をトリフルオロ酢酸（132μl）、及び塩化メチレン（3.9mL）の混合物で処理した。室温で1時間30分撹拌後、トリフルオロ酢酸（132μl）を再び添加して、混合物を1時間以上撹拌した。溶媒を減圧下で蒸発させて、トルエンと共に同時蒸発させた。粗製混合物をシリカゲルカラムクロマトグラフィーで精製し（溶出剤：塩化メチレン中のメタノール[0〜10%］の段階勾配）、凍結乾燥させ、白色粉末としてB390（36.4mg、21%）を得た。

(Example 22)
Preparation of hydroxy-tBuSATE N-benzyl phosphoramidate derivative of B390, 2'-C-methyl-2 ', 3'-di-O-acetyl-cytidine

Synthesis scheme:

To a solution of pronucleotide 13 (see Example 2, Procedure A, Strategy b) (300 mg, 0.27 mmol) in acetonitrile anhydride, triethylamine (92 μl) acetic anhydride (2.2 eq, 54 μl), and 4-dimethyl Aminopyridine (0.1 eq, 4 mg) was added sequentially. The reaction mixture was stirred at room temperature for 2 hours and triethylamine (92 μl), acetic anhydride (2.2 eq, 54 μl), and 4-dimethylaminopyridine (0.1 eq, 4 mg) were added again. After removal of the solvent under reduced pressure, the crude mixture was purified by silica gel column chromatography (eluent: step gradient of methanol [0-5%] in methylene chloride) and fully protected pronucleotide (329 mg, quantitative Yield). Finally, the compound was treated with a mixture of trifluoroacetic acid (132 μl) and methylene chloride (3.9 mL). After stirring for 1 hour 30 minutes at room temperature, trifluoroacetic acid (132 μl) was added again and the mixture was stirred for more than 1 hour. The solvent was evaporated under reduced pressure and coevaporated with toluene. The crude mixture was purified by silica gel column chromatography (eluent: step gradient of methanol [0-10%] in methylene chloride) and lyophilized to give B390 (36.4 mg, 21%) as a white powder.

2'-C-メチルシチジンのヒドロキシ-tBuSATE N-ベンジルホスホルアミダート 2',3'-環状カルボナート誘導体の合成
以下のストラテジーを合成のために使用した：

保護されたホスホラミダート13（1.72g、1.52mmol）をアルゴン下でジクロロメタン無水物（17mL）に溶解した。1,1'-カルボニルジイミダゾール（251mg、1.55mmol）を添加して、反応混合物をアルゴン下で室温にて1時間撹拌した。 (Example 23)
Preparation of B302

Synthesis of hydroxy-tBuSATE N-benzyl phosphoramidate 2 ', 3'-cyclic carbonate derivatives of 2'-C-methylcytidine The following strategy was used for the synthesis:

The protected phosphoramidate 13 (1.72 g, 1.52 mmol) was dissolved in anhydrous dichloromethane (17 mL) under argon. 1,1′-carbonyldiimidazole (251 mg, 1.55 mmol) was added and the reaction mixture was stirred at room temperature under argon for 1 hour.

Analysis by TLC (8% MeOH in DCM) showed incomplete conversion of starting material (Rf 0.35) to product (Rf 0.56). The profile was confirmed by HPLC analysis (Method Test 20, 272 nm): 9% starting material (Rt 7.30 min) and 91% product (Rt 7.97 min).
An additional portion of CDI (299 mg, 1.84 mmol, total) was added and the mixture was allowed to stir at room temperature for 24 hours, after which time analysis by HPLC showed 1.5% SM and 97.5% P .

The reaction mixture was evaporated in vacuo to give an off-white foam (1.97 g). Purify by silica gel plug column eluting with ethyl acetate and evaporate the appropriate fractions to give protected cyclic carbonate 14 (C ₆₅ H ₆₅ N ₄ O ₁₂ PS as white foam (1.62 g, 92%, yield)). 1157.27 gmol ^-1 ) was obtained.

  The protected cyclic carbonate 14 (1.50 g, 1.30 mmol) was dissolved in anhydrous dichloromethane (15 mL) at room temperature under argon. Pure trifluoroacetic acid (1.77 g, 15.5 mmol) was added dropwise to the reaction mixture and then stirred at room temperature for 45 minutes. Analysis by HPLC (Method Test 20, 272 nm) showed the disappearance of starting material (Rt 7.97 min) and the formation of product (Rt 3.80 min).

  Anhydrous methanol (5 mL) was added to the reaction mixture and the solvent (10 mL) was partially removed at 25 ° C. in vacuo. Additional methanol (7 mL) was added to the mixture which was then evaporated to give an orange residue. Trituration with hexane / TBME 3: 2 (12 mL) for 20 min added to the opaque supernatant to give a sticky residue that was decanted. Triturated again with hexane / TBME 3: 2 (5 mL) for 1 hour to remove the second supernatant and give a light foam (1.18 g) after co-evaporation with methanol (3 mL).

The crude foam was purified by reverse phase chromatography (packed in 1 mL acetonitrile and eluted with 0%, 10%, 15%, 20%, 25%, 30% acetonitrile in water). The relevant fractions were combined and the solvent was evaporated (1 mL) at 25 ° C. and chasing with ethanol to give cyclic carbonate 15, B302 as a white foam solid (560 mg, 71%, yield).

以下のストラテジーを合成のために使用した：

Boc保護されたバリン（6.72g、30.94mmol）をDCM無水物（50mL）に溶解して、1,1'-カルボニルジイミダゾール（4.87g、30.01mmol）をアルゴン下で室温にて添加した。気体の活発な発生が、活性化工程の間の最初に観察され、混合物を室温で30分間撹拌した。 (Example 24)
Preparation of hydroxy-tBuSATE N-benzyl phosphoramidate derivatives of B234, 3'-OL-valinyl-2'-C-methylcytidine

The following strategy was used for synthesis:

Boc protected valine (6.72 g, 30.94 mmol) was dissolved in DCM anhydride (50 mL) and 1,1′-carbonyldiimidazole (4.87 g, 30.01 mmol) was added at room temperature under argon. A vigorous evolution of gas was first observed during the activation process and the mixture was stirred at room temperature for 30 minutes.

  The protected phosphoramidate 13 (10.0 g, 8.84 mmol) was dissolved in anhydrous dichloromethane (50 mL) in a separate vessel under argon. The activated Boc-Val solution was added dropwise to the phosphoramidate solution and the resulting mixture was heated to 40 ° C. for 24 hours under argon.

  Analysis by TLC (8% MeOH in DCM) showed complete conversion of starting material 13 (Rf 0.35) to product (Rf 0.50). The profile was confirmed by HPLC analysis (Method Test 20, 272 nm): starting material (Rt 7.30 min) and product (Rt 9.46 min).

The reaction mixture was evaporated in vacuo to give an off-white foam. Purification by silica gel column chromatography (packed from DCM) eluting with ethyl acetate / hexane 1: 1 then 100% ethyl acetate and evaporation of appropriate fractions as white foam (10.3 g, 88%, yield) The protected valine ester 16 (C ₇₄ H ₈₄ N ₅ O ₁₄ PS 1330.52 gmol ⁻¹ ) was obtained.

  The protected valine ester 16 (3.0 g, 2.25 mmol) was dissolved in anhydrous dichloromethane (22.5 mL) at room temperature under argon. Pure trifluoroacetic acid (4.5 mL, 58.4 mmol) was added dropwise to the reaction mixture over 3 minutes and then stirred at room temperature for 1 hour. Analysis by HPLC (Method Test 20, 272 nm) showed disappearance of starting material (Rt 9.46 min) and formation of product (Rt 3.33 min) with significant Boc intermediate (Rt 4.60 min).

  Additional pure trifluoroacetic acid (1.0 mL, 13.0 mmol) was added dropwise to the reaction mixture and then stirred for an additional hour at room temperature. Analysis by HPLC (Method Test 20, 272 nm) showed the disappearance of the Boc intermediate (Rt 4.60 min) and the formation of the product (Rt 3.33 min).

  The reaction mixture was cooled to 5 ° C. and anhydrous methanol (50 mL) was added and stirred for 30 minutes. The solvent was removed in vacuo at 25 ° C. The residue was treated with TBME (50 mL × 3), triturated, and the TBME solution was decanted 3 times.

  The remaining material was dissolved in anhydrous methanol (5 mL) and DCM anhydrous (10 mL) and solid sodium bicarbonate (5 g) was added and stirred for 30 minutes to show pH 6. A clear liquid was passed through the syringe filter. The remaining solid bicarbonate was washed with 25% methanol in DCM (anhydrous, 10 mL) and the solution was filtered again. The combined filtrate was concentrated in vacuo to give crude 17 (2.15 g).

The crude material was purified by reverse phase chromatography (packed in 15 mL water and 3 mL acetonitrile and eluted with 0%, 5%, 20%, 30% acetonitrile in water). The relevant fractions were combined and the solvent was evaporated at 25 ° C. to give valine ester 17 (B234) as a white foam solid (737 mg, 48%, yield).

合成スキーム：

(Example 25)
Preparation of hydroxy-tBuSATE N-benzyl phosphoramidate derivative of B183, 2′-C-methyl-NH-4-acetyl-cytidine:

Synthesis scheme:

To a solution of B102 (see Example 2) (Compound 10, 200 mg, 0.34 mmol) in dimethylformamide anhydride (3.4 mL) was added acetic anhydride (1.1 eq, 34 μl) dropwise. The reaction mixture was stirred at room temperature for 4 hours and 10 μl of acetic anhydride was added again. The reaction mixture was stirred overnight and the solvent was evaporated under reduced pressure. The crude mixture was purified by silica gel column chromatography (eluent: step gradient of methanol [0-10%] in methylene chloride) and isolated as a white lyophilized powder, the desired acetylated pronucleotide B183 (169 mg, 79%) was obtained.

合成スキーム：

四塩化炭素無水物（13mL）中の化合物8（実施例2、手順A、ストラテジーaを参照されたい）（1.4g、1.3mmol）の溶液に、N-2-(トリフルオロメチル）ベンジルアミン（10eq、2.3g）を滴状に添加した。反応混合物を室温で3時間撹拌して、溶媒を減圧下で除去した。粗製混合物をシリカゲルカラムクロマトグラフィーで精製し（溶出剤：塩化メチレン中の[0-3%］メタノール段階勾配）、泡（60%）として所望の保護されたヌクレオシドを得た。この化合物を実施例2、ストラテジーAにおいて記述した実験条件に従ってホスホラミダートプロドラッグB187（245mg、35%）に変換し、白い凍結乾燥粉末として単離した。

(Example 26)
Preparation of hydroxy-tBuSATE N- (2- (trifluoromethyl) benzyl) phosphosphoramidate derivative of B187, 2'-C-methylcytidine

Synthesis scheme:

To a solution of compound 8 (see Example 2, Procedure A, Strategy a) (1.4 g, 1.3 mmol) in carbon tetrachloride anhydride (13 mL) was added N-2- (trifluoromethyl) benzylamine ( 10 eq, 2.3 g) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours and the solvent was removed under reduced pressure. The crude mixture was purified by silica gel column chromatography (eluent: [0-3%] methanol step gradient in methylene chloride) to give the desired protected nucleoside as a foam (60%). This compound was converted to phosphoramidate prodrug B187 (245 mg, 35%) according to the experimental conditions described in Example 2, Strategy A and isolated as a white lyophilized powder.

合成スキーム：

四塩化炭素無水物（10mL）中の化合物8（実施例2、手順A、ストラテジーaを参照されたい）（1.0g、0.94mmol）の溶液に、N-4-トリフルオロメチルベンジルアミン（5eq、670μl）を滴状に添加した。反応混合物を室温で3時間撹拌し、溶媒を減圧下で除去した。粗製混合物をシリカゲルカラムクロマトグラフィーで精製し（溶出剤：塩化メチレン中の[0-5%］メタノール段階勾配）、泡（84%）として所望の保護されたヌクレオシドを得た。この化合物を実施例2ストラテジーAにおいて記述した実験条件に従ってホスホラミダートプロドラッグB399（204mg、40%）に変換し、白い凍結乾燥粉末として単離した。

(Example 27)
Preparation of hydroxy-tBuSATE N- (4- (trifluoromethyl) benzyl) phosphosphoramidate derivative of B399, 2'-C-methylcytidine:

Synthesis scheme:

To a solution of compound 8 (see Example 2, Procedure A, Strategy a) (1.0 g, 0.94 mmol) in carbon tetrachloride anhydride (10 mL) was added N-4-trifluoromethylbenzylamine (5 eq, 670 μl) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours and the solvent was removed under reduced pressure. The crude mixture was purified by silica gel column chromatography (eluent: [0-5%] methanol step gradient in methylene chloride) to give the desired protected nucleoside as a foam (84%). This compound was converted to phosphoramidate prodrug B399 (204 mg, 40%) according to the experimental conditions described in Example 2 Strategy A and isolated as a white lyophilized powder.

合成スキーム：

四塩化炭素無水物（9mL）中の化合物8（実施例2、手順A、ストラテジーaを参照されたい）（950mg、0.89mmol）の溶液に、n-メチル-n-オクチルアミン（10eq、1.28g）を滴状に添加した。反応混合物を室温で3時間撹拌し、溶媒を減圧下で除去した。粗製混合物をシリカゲルカラムクロマトグラフィーで精製し（溶出剤：塩化メチレン中の[0-3%］メタノールの段階勾配）、泡（88%）として所望の保護されたヌクレオシドを得た。この化合物を実施例2ストラテジーAにおいて記述し実験条件に従ってホスホラミダートプロドラッグB204（52mg、7%）に変換し、白い凍結乾燥粉末として単離した。

(Example 28)
Preparation of hydroxy-tBuSATE N- (n-methyl-n-octyl-amine) phosphophosphoramidate derivatives of B204, 2'-C-methylcytidine

Synthesis scheme:

To a solution of compound 8 (see Example 2, Procedure A, Strategy a) (950 mg, 0.89 mmol) in carbon tetrachloride anhydride (9 mL) was added n-methyl-n-octylamine (10 eq, 1.28 g ) Was added dropwise. The reaction mixture was stirred at room temperature for 3 hours and the solvent was removed under reduced pressure. The crude mixture was purified by silica gel column chromatography (eluent: [0-3%] methanol step gradient in methylene chloride) to give the desired protected nucleoside as a foam (88%). This compound was converted to phosphoramidate prodrug B204 (52 mg, 7%) according to the experimental conditions described in Example 2 Strategy A and isolated as a white lyophilized powder.

合成スキーム：

四塩化炭素無水物（15mL）中の化合物12（実施例2、手順A、ストラテジーbを参照されたい）（1.5g、1.46mmol）の溶液に、ジブチルアミン（10eq、2.5mL）を滴状に添加した。反応混合物を室温で3時間撹拌し、溶媒を減圧下で除去した。粗製混合物をシリカゲルカラムクロマトグラフィーで精製し（溶出剤：塩化メチレン中の[0-5%］メタノールの段階勾配）、泡（61%）として所望の保護されたヌクレオシドを得た。この化合物を実施例2ストラテジーBにおいて記述し実験条件に従ってホスホラミダートプロドラッグB244（21mg、4%）に変換し、白い凍結乾燥粉末として単離した。

(Example 29)
Preparation of hydroxy-tBuSATE N, N- (dibutylamine) phosphoramidate derivatives of B244, 2'-C-methylcytidine

Synthesis scheme:

To a solution of compound 12 (see Example 2, Procedure A, Strategy b) (1.5 g, 1.46 mmol) in carbon tetrachloride anhydride (15 mL) is added dibutylamine (10 eq, 2.5 mL) dropwise. Added. The reaction mixture was stirred at room temperature for 3 hours and the solvent was removed under reduced pressure. The crude mixture was purified by silica gel column chromatography (eluent: step gradient of [0-5%] methanol in methylene chloride) to give the desired protected nucleoside as a foam (61%). This compound was converted to phosphoramidate prodrug B244 (21 mg, 4%) according to the experimental conditions described in Example 2 Strategy B and isolated as a white lyophilized powder.

合成スキーム：

四塩化炭素無水物（26mL）中の化合物12（実施例2、手順A、ストラテジーbを参照されたい）（2.7g、2.6mmol）の溶液に、N-ベンジルメチルアミン（5eq、1.67mL）を滴状に添加した。反応混合物を室温で3時間撹拌し、溶媒を減圧下で除去した。粗製混合物をシリカゲルカラムクロマトグラフィーで精製し（溶出剤：塩化メチレン中の[0-5%］メタノールの段階勾配）、泡（44%）として所望の保護されたヌクレオシドを得た。この化合物を実施例2ストラテジーBにおいて記述した実験条件に従ってホスホラミダートプロドラッグB308（43mg、2%）に変換し、白い凍結乾燥粉末として単離した。

(Example 30)
Preparation of hydroxy-tBuSATE N-methylbenzyl phosphophosphoramidate derivative of B308, 2'-C-methylcytidine

Synthesis scheme:

To a solution of compound 12 (see Example 2, Procedure A, Strategy b) (2.7 g, 2.6 mmol) in carbon tetrachloride anhydride (26 mL) is added N-benzylmethylamine (5 eq, 1.67 mL). Added dropwise. The reaction mixture was stirred at room temperature for 3 hours and the solvent was removed under reduced pressure. The crude mixture was purified by silica gel column chromatography (eluent: step gradient of [0-5%] methanol in methylene chloride) to give the desired protected nucleoside as a foam (44%). This compound was converted to phosphoramidate prodrug B308 (43 mg, 2%) according to the experimental conditions described in Example 2 Strategy B and isolated as a white lyophilized powder.

合成スキーム：

四塩化炭素無水物（3mL）中の化合物12（実施例2、手順A、ストラテジーbを参照されたい）（300mg、0.29mmol）の溶液に、ピペリジン（5eq、145μl）を滴状に添加した。反応混合物を室温で3時間撹拌し、溶媒を減圧下で除去した。粗製混合物をシリカゲルカラムクロマトグラフィーで精製し（溶出剤：塩化メチレン中の[0-5%］メタノールの段階勾配）、泡（55%）として所望の保護されたヌクレオシドを得た。この化合物を実施例2ストラテジーBにおいて記述した実験条件に従ってホスホラミダートプロドラッグB353（19mg、22%）に変換し、白い凍結乾燥粉末として単離した。

(Example 31)
Preparation of hydroxy-tBuSATE N-piperidine phosphophosphoramidate derivatives of B353,2'-C-methylcytidine

Synthesis scheme:

Piperidine (5 eq, 145 μl) was added dropwise to a solution of compound 12 (see Example 2, Procedure A, strategy b) (300 mg, 0.29 mmol) in anhydrous carbon tetrachloride (3 mL). The reaction mixture was stirred at room temperature for 3 hours and the solvent was removed under reduced pressure. The crude mixture was purified by silica gel column chromatography (eluent: step gradient of [0-5%] methanol in methylene chloride) to give the desired protected nucleoside as a foam (55%). This compound was converted to phosphoramidate prodrug B353 (19 mg, 22%) according to the experimental conditions described in Example 2 Strategy B and isolated as a white lyophilized powder.

合成スキーム：

四塩化炭素無水物（3mL）中の化合物12（実施例2、手順A、ストラテジーbを参照されたい）（300mg、0.29mmol）の溶液に、シクロヘキシルアミン（5eq、170μl）を滴状に添加した。反応混合物を室温で3時間撹拌し、溶媒を減圧下で除去した。粗製混合物をシリカゲルカラムクロマトグラフィーで精製し（溶出剤：塩化メチレン中の[0-5%］メタノールの段階勾配）、泡（55%）として所望の保護されたヌクレオシドを得た。この化合物を実施例2ストラテジーBにおいて記述した実験条件に従ってホスホラミダートプロドラッグB354（44mg、50%）に変換し、白い凍結乾燥粉末として単離した。

(Example 32)
Preparation of hydroxy-tBuSATE N-cyclohexylamine phosphophosphoramidate derivatives of B354, 2'-C-methylcytidine

Synthesis scheme:

To a solution of compound 12 (see Example 2, Procedure A, Strategy b) (300 mg, 0.29 mmol) in anhydrous carbon tetrachloride (3 mL), cyclohexylamine (5 eq, 170 μl) was added dropwise. . The reaction mixture was stirred at room temperature for 3 hours and the solvent was removed under reduced pressure. The crude mixture was purified by silica gel column chromatography (eluent: step gradient of [0-5%] methanol in methylene chloride) to give the desired protected nucleoside as a foam (55%). This compound was converted to phosphoramidate prodrug B354 (44 mg, 50%) according to the experimental conditions described in Example 2 Strategy B and isolated as a white lyophilized powder.

合成スキーム：

四塩化炭素無水物（3.4mL）中の化合物12（実施例2、手順A、ストラテジーbを参照されたい）（350mg、0.34mmol）の溶液に、モルホリン（10eq、300μl）を滴状に添加した。反応混合物を室温で3時間撹拌し、溶媒を減圧下で除去した。粗製混合物をシリカゲルカラムクロマトグラフィーで精製し（溶出剤：塩化メチレン中の[0-5%］メタノールの段階勾配）、泡（70%）として所望の保護されたヌクレオシドを得た。この化合物を実施例2ストラテジーBにおいて記述した実験条件に従ってホスホラミダートプロドラッグB391（53mg、49%）に変換し、白い凍結乾燥粉末として単離した。

(Example 33)
Preparation of hydroxy-tBuSATE N-morpholinophosphosphoramidate derivatives of B391, 2'-C-methylcytidine

Synthesis scheme:

To a solution of compound 12 (see Example 2, Procedure A, Strategy b) (350 mg, 0.34 mmol) in carbon tetrachloride anhydride (3.4 mL) was added morpholine (10 eq, 300 μl) dropwise. . The reaction mixture was stirred at room temperature for 3 hours and the solvent was removed under reduced pressure. The crude mixture was purified by silica gel column chromatography (eluent: step gradient of [0-5%] methanol in methylene chloride) to give the desired protected nucleoside as a foam (70%). This compound was converted to phosphoramidate prodrug B391 (53 mg, 49%) according to the experimental conditions described in Example 2 Strategy B and isolated as a white lyophilized powder.

合成スキーム：

四塩化炭素無水物（5mL）中の化合物12（実施例2、手順A、ストラテジーbを参照されたい）（500mg、0.49mmol）の溶液に、ピロリジン（5eq、200μl）を滴状に添加した。反応混合物を室温で3時間撹拌し、溶媒を減圧下で除去した。粗製混合物をシリカゲルカラムクロマトグラフィーで精製し（溶出剤：塩化メチレン中の[0-5%］メタノールの段階勾配）、泡（87%）として所望の保護されたヌクレオシドを得た。この化合物を実施例2ストラテジーBにおいて記述した実験条件に従ってホスホラミダートプロドラッグB395（48mg、21%）に変換し、白い凍結乾燥粉末として単離した。

Example 34
Preparation of hydroxy-tBuSATE N-pyrrolidine phosphophosphoramidate derivatives of B395, 2'-C-methylcytidine

Synthesis scheme:

To a solution of compound 12 (see Example 2, Procedure A, Strategy b) (500 mg, 0.49 mmol) in anhydrous carbon tetrachloride (5 mL) was added pyrrolidine (5 eq, 200 μl) dropwise. The reaction mixture was stirred at room temperature for 3 hours and the solvent was removed under reduced pressure. The crude mixture was purified by silica gel column chromatography (eluent: [0-5%] methanol step gradient in methylene chloride) to give the desired protected nucleoside as a foam (87%). This compound was converted to phosphoramidate prodrug B395 (48 mg, 21%) according to the experimental conditions described in Example 2 Strategy B and isolated as a white lyophilized powder.

(Example 35)
Anti-HBV activity The compound of Example 1 (NM 204) (hydroxy-tBuSATE N-benzyl phosphoramidate derivative of L-ddA) (A550) was contacted with HepG2 cells infected with HBV. EC ₅₀ values were measured according to standard techniques. As shown in the table below, the compound of Example 1 showed significant activity compared to the parent molecule LddA.

Example 36
Calibration curve preparation for the measurement of ddATP
2'-3'-dideoxyadenosine-5'-triphosphate (ddATP) (2'-3'-dideoxyadenosine (ddA) triphosphate nucleotide is a liquid chromatography tandem mass spectrometric analysis of, for example, a hepatocyte methanol extract. (LC / MS / MS).

  The concentration of ddATP is measured by comparison against a standard curve.

A working stock solution of TP-ddA is prepared from a 100 pmol / μl stock solution in deionized water of ddATP (> 91% purity tetrasodium salt) purchased from Sigma Chemical Co as follows:
Preparation of ddATP working stock and standard curve for ddATP

An internal standard (ISTD) working stock was prepared from a 0.50 mg / mL stock of 2-deoxyadenosine 5-triphosphate purchased from Sigma Chemical.

を使用して以下の通りに調製する。 In some embodiments, the calibration standard is

Is prepared as follows.

  In some embodiments, the following HPLC conditions are used for HPLC MS (eg, HPLC tandem MS analyzer method).

HPLC is performed on a Phenomenex Luna Amino 3 μm 100A, 30 × 2 mm column with mobile phase A: 70% 10 mM NH ₄ OAc 30% ACN pH 6.0; and B: 70% 1 mM NH ₄ OAc 30% ACN pH 10.5 as follows:

(Example 37)
In vitro phosphorylation in hepatocytes Primary hepatocytes (rats, cynomolgus monkeys or humans) are seeded at 0.8 × 10 ⁶ in collagen-coated 12-well plates and allowed to adhere for 4-6 hours, after which time the inoculum medium Was replaced with serum free medium and the cells were allowed to acclimate to fresh medium overnight. The next day, cells were prepared against 10 and 50 μM specimens (NM204) (A550) prepared in fresh culture from stock in DMSO (final DMSO concentration was 0.1%). Exposed for 1, 4, 8, and 24 hours. At each time point, an aliquot (500 μl) was collected and 500 μl acetonitrile was added immediately and stored at −2 ° C. until analysis. The remaining exposure medium was removed and the cell monolayer (attached to the dish) was washed twice with ice-cold PBS. Any remaining PBS was carefully removed by aspiration and the cells were collected by scraping in 1 mL 70% ice-cold methanol. Cell samples were placed overnight at −20 ° C. and cell debris was removed by centrifugation the next day. The supernatant was removed and analyzed prior to analysis by LC / MS. A standard curve was prepared by using similarly treated untreated cells, but before collecting in 70% methanol, 10 μl of LddATP standard solution prepared in methanol was added to the washed monolayer. Except that. These control samples were then processed and analyzed as described for the test samples.

The results are shown below:

  As indicated by the data, a significant level of L-ddATP was detected in hepatocytes. In monkey hepatocytes, levels appear to reach a maximum level at 8 hours and then decline rapidly. In contrast, both rat and human hepatocyte levels appear to level off after 8 hours.

(Example 38)
In vivo studies in rats The distribution of NM-204 (Example 1 (hydroxy-tBuSATE N-benzyl phosphoramidate derivative of L-ddA) (A550) in rat liver, 20 (oral), or 10 (IV) mg in rat liver Evaluated after single intravenous (intravenous) or oral administration of A550 (NM-204) at a dose of / kg body weight A dose solution was prepared on the same day before dose administration.

At specific time points (1 and 3 hours for IV animals, or 1, 3 and 8 hours for oral animals), each animal is euthanized by CO ₂ gas followed by blood loss via the abdominal vein. It was. Livers were collected immediately after smearing, snap frozen in liquid nitrogen, placed on dry ice and then stored at -70 ° C until analysis.

Preparation of calibration standards from control liver extract:
Control rat liver samples were taken from whole frozen livers (Bioreclamation, Inc. Hicksville, NY) using a tool to detach tissue from the center (Harris Unicore, 8.0 mm, VWR). Each ~ 0.1 g sample is placed in an individual 2 mL polyvial containing 0.940 mL 80% MeOH / 20% DIH ₂ O and the homogenate is mechanical tissue plasters (Tissue Master, Omni-Internationa1, Inc, Marietta GA) Was used to prepare. The vial was vortexed for 30 seconds after receiving an aliquot of 10 μl working stock and an aliquot of 50 μl ISTD. The mixture was stored at −20 ° C. overnight and the next day it was removed for 10 minute centrifugation in a tabletop centrifuge. Each supernatant was transferred to an individual centrifugal filtration unit (0.45 μm) and the resulting filtrate was transferred to an HPLC vial for LC / MS / MS analysis. The final concentrations of ddATP in the calibration standard were 1000, 500, 250, 125, 50, and 0 pmol / mL. Each calibration standard was directly injected in a 50 μL volume onto an ion exchange column for analysis. A standard curve analysis of calibration standards from control liver extracts was performed.

The analysis of ddATP was performed by ion exchange chromatography in on-line positive ionization ESI-MS / MS detection and in multiple reaction monitoring (MRM) detection mode. With the peak areas obtained for four of the five calibrators, a standard curve can be constructed that exhibits excellent linearity (R ² = 0.9996) over a concentration range of 50-1000 pmol / mL. This leads to a range of 5-100 pmol per gram of liver, depending on the sample preparation used. The HPLC MS MS conditions described in Example 5 were utilized. The lower limit of quantification shown by the LC / MS / MS method is, for example, ˜0.2 pmol / mL for cell extracts of hepatocytes containing much less salt.

Results showing intracellular levels of A550 (NM204) (indicating compounds that entered hepatocytes) and LddATP (indicating phosphoramidate part of ddA to triphosphate active in liver and triphosphorylation) are shown below. Shown in:

  Thus, these results indicate that the compounds can be used to enhance the concentration of drug in the liver. These results also show an enhanced concentration of active triphosphate formed in hepatocytes.

(Example 39)
HCV replicon assay
Huh-7 cells (GS4.1 cells) containing HCV Con1 subgenomic replicons (C. Seeger; Fox Chase University, Philadelphia, PA, USA) are 10% fetal bovine serum (FBS), 2 mM L-glutamine, 110 mg / Culture in Dulbecco's modified Eagle's medium (DMEM) supplemented with L sodium pyruvate, 1x non-essential amino acids, 100 U / mL penicillin-streptomycin, and 0.5 mg / mL G418 (Invitrogen). For dose response studies, cells were seeded in 96 well plates at a volume of 50 μL at 7.5 × 10 ³ cells / well and incubated at 37 ° C./5% CO ₂ . Three hours after seeding, 50 μL is added with 10 2-fold serial dilutions of the compound (maximum concentration, 75 μM) and the cell culture is incubated at 37 ° C./5% CO ₂ in the presence of 0.5% DMSO. did. Alternatively, compounds are tested at a single concentration of 15 μM. In all cases, Huh-7 cells lacking the HCV replicon served as a negative control. Cells are incubated for 72 hours in the presence of compounds, after which they are monitored for expression of NS4A protein by enzyme-linked antibody immunosorbent assay (ELISA). To do this, the plates are then fixed with 1: 1 acetone: methanol for 1 minute, washed twice with phosphate buffered saline (PBS), 0.1% Tween 20, and room temperature with TNE buffer containing 10% FBS. And then incubated with anti-NS4A mouse monoclonal antibody A-236 (ViroGen) diluted in the same buffer for 2 hours at 37 ° C. After washing 3 times with PBS, 0.1% Tween 20, the cells are incubated for 1 hour at 37 ° C. with anti-mouse immunoglobulin G-peroxidase conjugated to TNE, 10% FBS. After washing as above, the reaction is developed with O-phenylenediamine (enzyme). The reaction is stopped after 30 minutes with 2N H ₂ SO ₄ and the absorbance is read at 492 nm using a Sunrise Tecan spectrophotometer. EC ₅₀ values are determined from% inhibition versus concentration data using sigmoidal non-linear regression analysis based on four parameters in Tecan Magellan software. When screening at a single concentration, the results are expressed as% inhibition at 15 μM. For cytotoxicity assessment, GS4.1 cells are treated with compounds as described above and cell viability is monitored using the Cell Titer 96 AQueous One Solution Cell Proliferation Assay (Promega). CC ₅₀ values are determined from% cytotoxicity versus concentration data with Tecan Magellan software as described above.

Results The compounds shown in the table below were assayed according to the replicon assay described above.

細胞傷害性、及び有効性は、コラーゲンプレート上で決定した。 (Example 40)
HBV drug sensitivity assay
a) Cells were seeded on a collagen-I coated culture plate at a density of 0.25-0.5 × 10 ⁶ cells per well in 2 mL of growth / selection medium.
b) The drug stock solution was newly prepared in 100% DMSO as a 20Ox stock solution. Prepared from 2.5 μM to 0.0006 μM (final) by seven 4-fold dilutions of test compound. The master drug dilution was divided into 4 aliquots and then stored at -20 ° C until use.
c) One day after seeding the cells, drug therapy was started by adding 10 μl of drug dilution with 2 mL of fresh growth / selection medium. Therefore, the final DMSO concentration did not exceed 0.5%. Control wells without drug received 10 μl DMSO in fresh medium.
d) Cells were treated with 2 mL of fresh drug combination / medium every other day for a total of 8 days. Cell lysates were then collected on day 10 as described below and subjected to endogenous polymerase assay.
Preparation of nucleocapsid-containing solubilizer for EPA analysis
a) Cells were collected 2 days after the final drug therapy.
b) The medium was carefully aspirated and the cell monolayer was rinsed once with 1 mL PBS.
c) 1 mL of lysis buffer (50 mM Tris-HCl pH 7.5 / 150 mM NaCl / 5 mM MgCl ₂ /0.2% NP-40) was added to each well. A detergent is required to strip the outer membrane from the virion and allow capture of the inner nucleocapsid. Plates were kept on ice for> 30 minutes.
d) Solubilized cells were transferred to 1.5 mL-microcentrifuge tubes.
e) The lysate was clarified by spinning at 14,000 rpm for 5 minutes at room temperature.
f) The clarified lysate is transferred to a fresh tube and immediately frozen on dry ice and then stored at -80 ° C. until an endogenous polymerase assay can be performed as described below .
Cellular lysate endogenous polymerase assay (EPA)
a) EPA was performed essentially as described in Seifer et al. (1998) J. Virol. 72: 2765-2776. The clarified lysate was thawed at room temperature.
b) Intracellular HBV nucleocapsid was immunoprecipitated from cytosolic lysate overnight at 4 ° C. with polyclonal rabbit anti-HBcAg antibody and immobilized on Protein A Sepharose CL-4B beads.
c) After two washes of capsid fixed with 1 mL EPA wash buffer (75 mM NH ₄ Cl, 50 mM Tris-HCl pH 7.4, 1 mM EDTA), 50 μl detergent-containing EPA cocktail (50 mM Tris-HCl pH 7. ₄ , 75 mM NH ₄ Cl, 1 mM EDTA, 20 mM MgCl ₂ , 0.1 mM β-ME, 0.5% NP-40, 100 μM chilled dGTP, TTP, dCTP, and 50 nM ³³ P-dATP) Start and incubate overnight at 37 ° C. A detergent is required to enhance the permeability of the nucleocapsid.
d) Following digestion with 1 mg / mL proteinase K for 1 hour at 37 ° C., endogenously ³³ P-labeled HBV DNA was released by phenol / chloroform extraction.
e) The nucleic acids were then precipitated with 1 volume of 5M NH ₄ -acetate and 2.5 volumes 100% EtOH and separated on a 1% native agarose gel in Tris-borate buffer.
f) The gel was blotted onto a positively charged nylon membrane overnight at room temperature via a capillary transition in 0.4N NaOH.
g) The dried membrane was exposed to a phosphoimager screen (GE Healthcare) overnight at room temperature, then scanned (Storm 860, GE Healthcare) and quantified with ImageQuant software (GE Healthcare).
h) Dose response curves were generated using XLfit 4.1 software. The mean effective pressure drug concentration that inhibits endogenous HBV polymerase activity by 50% was calculated from several independent experiments.
Cytotoxicity determination Standard in vitro cytotoxicity assays were performed on HepG2 cells. Cells were exposed to drug for 9 days. Cell viability was determined via MTS staining using the CellTiter96Aqueous One Solution cell proliferation assay according to the manufacturer's instructions.
a) HepG2 cells were seeded in 96-well tissue culture plates in 100 μl of initial growth medium at 7 × 10 ³ cells per well.
b) A drug stock solution was prepared in 100% DMSO as a 40O × stock solution and stored at −20 ° C. until use.
c) Four hours after cells were plated, drug dilutions were prepared and then added to the cells. Cells received up to 100 μM drug in fresh growth medium containing a total of 200 μl of 0.25% DMSO. Control wells received growth medium with 0.25% DMSO growth medium. Plates were incubated at 37 ° C., 5% CO ₂ .
d) Cells were treated every other day with fresh growth media and fresh drug dilution for a total of 8 days as described above.
e) On day 9, the cell viability of HepG2 cells was determined by adding 20 μl of MTS CellTiter96Aqueous One Solution. After incubation at 37 ° C. for 4 hours, the absorbance was measured at A ₄₉₀ nm in a Victor V plate reader (Perkin Elmer).
f) CC ₅₀ concentration was determined using XLfit 4.1 software.
Antiviral agent in vitro activity of PMEA, B261 (PMEA hydroxy-tBuSATE N-benzyl phosphoramidate derivative as shown in Table 10), together with LdT as a control, a total of 4 HBV drug sensitivity assays Tested. The table below provides the results:

Cytotoxicity and efficacy were determined on collagen plates.

(Example 41)
Determination of total metabolism in intracellular fraction of hepatocytes (parent depletion)
NADPH incubation. Microsomes, or S9 incubation was performed in a final volume of 0.5 mL. Incubation buffer (10OmM potassium phosphate, pH 7.4,5mM MgCl _2, and 0.1 mM EDTA) pooled liver microsomes suspended in, or S9 protein (1.0 mg / mL), stock solution in DMSO (final DMSO concentration Was 0.1%) and pre-incubated with 10-50 μM OHSATE phosphoramidate compound at 37 ° C. for 5 minutes; the reaction was initiated by the addition of NADPH (3 mM final concentration). Incubation without NADPH served as a control. At specified times (0-120 minutes), a 0.1 mL sample was taken and the reaction was terminated by the addition of 1 volume of stop solution (acetonitrile). The sample was texed for 30 seconds and then centrifuged at 1500 g for 10 minutes. The supernatant was transferred to an HPLC glass vial and analyzed by HPLC without further processing. Figures 1 and 2 show depletion of NM108 SATE phosphoramidate (B299) and NM107 SATE phosphoramidate (B102), respectively, after incubation with monkey liver S9 NADPH.

  Thus, without being limited to any theory, metabolism is NADPH-dependent, so phosphoramidate compounds may be preferentially activated by cytochrome P450 in the liver.

(Example 42)
Determination of triphosphate levels in cells Preparation of primary hepatocyte cultures Animals and freshly isolated cells from human liver were obtained in suspension on ice. After receipt, the cells were pelleted by centrifugation at 500 rpm (rats) or 700 rpm (monkeys and humans) and resuspended at 800,000 cells per mL of plating medium (HPM). The plates were then seeded by adding 1 mL of cell suspension (800,000 cells / mL) to a multiwell collagen-coated plate (12-well). The plate was gently shaken to distribute the cells uniformly and placed in a 37 ° C. incubator for approximately 4-6 hours to allow the cells to adhere. Once the cells adhered, the plating medium was removed and replaced with hepatocyte culture medium (HCM). The cells were left in the incubator at 37 ° C. overnight to adapt to the culture and medium.

Incubation with test substances Hepatocyte incubation was performed in a final volume of 1.0 mL HCM / well (800,000 cells / mL). HCM from the overnight incubation of cells was removed and replaced with fresh HCM preheated to 37 ° C. containing 10 μM test substance from stock in DMSO (final DMSO concentration was 0.1%). At specified times (up to 24 hours), the incubation medium was discarded and the cell monolayer was carefully washed twice with ice-cold PBS. After the last wash, all PBS was carefully removed and 1 mL of extraction buffer (ice-cold 70% methanol) was added. Each well was sealed with parafilm immediately after the addition of methanol. Once all the plates were processed, additional parafilm was placed on all the plates to form a double seal to prevent evaporation during the extraction process. The cover lid was then placed on the plate and sealed with tape. The plates were then stored at −2 ° C. for a minimum of 24 hours so that intracellular content could be extracted.

Preparation of Huh7 or HepG2 culture
HepG2 or Huh7 cells were plated on collagen-coated 12-well plates at 0.4 × 10 ⁶ cells / well. Cells were allowed to adhere overnight. Remove medium from overnight incubation of cells and replace with fresh medium preheated to 37 ° C containing 10 μM test substance from stock in DMSO (final DMSO concentration was 0.1%) It was. After 24-72 hours, the incubation medium was discarded and the cell monolayer was carefully washed twice with ice-cold PBS. After the last wash, all PBS was carefully removed and 1 mL of extraction buffer (ice-cold 70% methanol) was added. Each well was sealed with parafilm immediately after the addition of methanol. Once all the plates were processed, additional parafilm was placed on all the plates to form a double seal to prevent evaporation during the extraction process. The cover lid was then placed on the plate and sealed with tape. The plates were then stored at −2 ° C. for a minimum of 24 hours so that intracellular content could be extracted.

Sample preparation for analysis Cell extracts were prepared by transferring 0.9 mL of extract to a 2 mL microtube followed by centrifugation at 14,000 rpm for 5 minutes. Approximately 100 μL of the supernatant was transferred to an HPLC vial and triphosphate levels were determined by LCMS / MS as described below.

HPLC conditions: NM107-triphosphate

Exemplary HPLC conditions: NM108-triphosphate

NML07 triphosphate and B102 triphosphate levels in cell extracts were observed as follows:

  As can be seen from the intracellular triphosphate data level for B102, it was higher compared to the intracellular triphosphate data level for NMl07.

(Example 43)
Demonstration of potent antiviral activity of B102, a second-generation nucleoside inhibitor, in chimpanzees infected with HCV
Nucleoside analogues such as NM107 (2 'methylcytidine, a valopicitabine nucleoside component) have shown efficacy against HCV in clinical settings, and these 5'-triphosphates (TP) are HCV NS5B It can be a potent inhibitor of polymerase. However, their wide systemic distribution and inefficient liver conversion to TP can lead to safety and reduced antiviral activity. The in vivo preclinical safety and antiviral activity of B102, a nucleotide prodrug, was evaluated.

  Methods: For pharmacokinetic (PK) and addiction studies, B102 was orally administered to rats or monkeys at doses of 20-300 mg / kg / day for up to 14 days. Liver nucleoside TP levels were determined by LC-MS / MS. The compound (10 mg / kg / day) was administered once daily by oral gavage for 4 days in chimpanzees chronically infected with HCV genotype 1. HCV viral load was monitored during and after treatment by quantitative RT-PCR.

  Results: PK studies in rats and monkeys revealed that B102 had> 95% first-pass liver extraction and low systemic exposure (<1%). Liver TP levels were 10-50 fold higher with nucleotide prodrugs versus nucleoside counterparts. Toxicity was not observed after 14 days administration of 50 mg / kg / day A2 to monkeys. No initial vomiting or GI toxicity was observed. In HCV-infected chimpanzees, B102 produced a rapid and potent antiviral effect, followed by recoil to baseline after drug interruption. The reduction in mean viral load ranged from 1.5 log10 for B102 over 4 days of drug exposure. The same dose of Valopicitabine resulted in a 0.7 log10 virus reduction. No evidence of rap enzyme abnormalities or toxicity was observed in chimpanzees.

  Thus, when administered orally, B102 produces high liver triphosphate levels associated with low systemic exposure, causing rapid and potent inhibition of HCV replication in chimpanzees, and thus promising in vivo preclinical safety. Profile and antiviral activity are shown.

(Example 44)
The compound was tested in an anti-HBV assay. Determination of anti-HBV activity on HBV virions and nucleocapsids by endogenous polymerase assay (EPA).
Drug sensitivity assay using wild type HBV producing cell line
1. Producer cells expressing wild type HBV were plated on 12-well collagen-I coated plates in 2 mL of growth / selection medium at a density of 0.5-1 × 10 ⁶ cells per well.
2. The drug stock solution was newly prepared in 100% DMSO as 20Ox stock solution. Five additional 4-fold dilutions were prepared from these 20Ox stocks in 100% DMSO. For each experiment, four aliquots of each series of drug dilutions were stored at −20 ° C. until use.
3. Once the cells reached confluency (1 day after seeding the cells), drug therapy was initiated by adding 10 μl of drug dilution to 2 mL of fresh growth / selection medium. Therefore, the final DMSO concentration did not exceed 0.5%. Control wells without drug received only 10 μl DMSO in fresh medium.
4. Cells were treated with 2 mL of fresh drug / medium every other day for a total of 8 days. Cell lysates were then collected on day 10 and subjected to EPA analysis as described below.
Preparation of nucleocapsid-containing solubilizer for EPA analysis
1. Cells were cultured for 3-4 days to confluence in 12-well collagen-I coated plates.
2. The medium was carefully aspirated and the cell monolayer was rinsed once with 1 mL of PBS.
3. 1 mL of lysis buffer (50 mM Tris-HCl pH 7.5 / 150 mM NaCl / 5 mM MgCl ₂ /0.2% NP-40) was added to each well. Plates were stored on ice for 30 minutes to 4 hours.
4. The lysed cells were transferred to a 1.5 mL-microcentrifuge tube.
5. The lysate was clarified by spinning at 14,000 rpm for 5 minutes at room temperature.
6. The clarified lysate was transferred to a fresh tube, snap frozen on dry ice, and then stored at −80 ° C. until the endogenous polymerase assay was performed as described below.
Preparation of virions secreted from supernatant for EPA analysis
1. Cells were cultured for 3-4 days to confluence in 12-well collagen-I coated plates.
2. The medium was carefully aspirated and transferred to a 1.5 mL microtube.
3. The supernatant was clarified by spinning at 14,000 rpm for 5 minutes at room temperature.
4. The clarified supernatant was transferred to a fresh tube, snap frozen on dry ice, and then stored at −80 ° C. until the endogenous polymerase assay was performed essentially as described below.
Cellular lysate and supernatant endogenous polymerase assay (EPA)
1. EPA was performed essentially as described in Seifer et al. (1998). Intracellular HBV nucleocapsid was immunoprecipitated from a cytosolic lysate overnight at 4 ° C. with a polyclonal rabbit anti-HBcAg antibody and immobilized on Protein A Sepharose CL-4B beads. Secreted virions were immunoprecipitated from the cleared cell supernatant with monoclonal mouse anti-LS antibody (MA18 / 7) overnight at 4 ° C. in the absence of detergent.
2. After 3 washes of immobilized capsid or virion with 1 mL EPA wash buffer (75 mM NH ₄ Cl, 50 mM Tris-HCl pH 7.4, 1 mM EDTA), 50 μl detergent-containing EPA cocktail (50 mM Tris -HCl pH 7.4, 75 mM NH ₄ Cl, 1 mM EDTA, 20 mM MgCl ₂ , 0.1 mM β-ME, 0.5% NP-40, 100 μM cooled dGTP, TTP, dCTP, and 50 nM ³³ P-dATP) Endogenous polymerase reaction was initiated and incubated overnight at 37 ° C. Detergents are required to remove the outer membrane from the immunoprecipitated virion as well as to enhance the permeability of the nucleocapsid.
3. Following digestion with 1 mg / mL proteinase K for 1 hour at 37 ° C., endogenous ³³ P-labeled HBV DNA was released by phenol / chloroform extraction.
4. Nucleic acids are precipitated with 1 volume of 5M NH ₄ -acetate and 2.5 volumes of 100% EtOH and then separated on a 1% native agarose gel in Tris-Borate-EDTA buffer.
5. The gel was blotted onto a positively charged nylon membrane overnight at room temperature via a capillary transition in 0.4N NaOH.
6. The dried membrane was exposed to a phosphoimager screen (GE Healthcare) overnight at room temperature, then scanned (Storm 860, GE Healthcare) and quantified with ImageQuant software (GE Healthcare).
7. The 50% effective concentration (EC ₅₀ ) value was calculated from the resulting best-fit equation determined by Xlfit, version 4.1 (IDB).

The following results were obtained.

29：｛9-[(2R）2-デオキシ-2-フルオロ-2-C-エチニル-β-D-エリスロ-フラノシル]-グアニン｝-5'-イル-O-(トリフェニルメチルオキシ-tert-ブチル- S -アシル-2-チオエチル)-H-ホスホナート
7j（0.32mmol）、及びS-(2-ホスファイト-エチル）2,2-ジメチル-3-トリフェニルメチルオキシ-チオプロピオナート（0.42mmol）のピリジン（5mL）中の撹拌溶液に、-15℃にて窒素下で塩化ピバロイル（0.64mmol）を滴状に添加した。反応混合物を-15℃にて2時間撹拌した。ジクロロメタン、及びNH₄Cl溶液を添加した。有機相を分離して、NH₄Cl溶液で洗浄し、Na₂SO₄上で乾燥させ、濾過して、減圧下で濃縮した。粗製物質をフラッシュカラムクロマトグラフィー（DCM/MeOH）によって精製し、表題化合物を得た。茶色粉末。

Example 45: Ethynyl nucleoside for the treatment of HCV An exemplary compound synthesis is described below:

29: {9-[(2R) 2-deoxy-2-fluoro-2-C-ethynyl-β-D-erythro-furanosyl] -guanine} -5′-yl-O- (triphenylmethyloxy-tert- Butyl-S-acyl-2-thioethyl) -H-phosphonate
To a stirred solution of 7j (0.32 mmol) and S- (2-phosphite-ethyl) 2,2-dimethyl-3-triphenylmethyloxy-thiopropionate (0.42 mmol) in pyridine (5 mL) was added- Pivaloyl chloride (0.64 mmol) was added dropwise at 15 ° C. under nitrogen. The reaction mixture was stirred at −15 ° C. for 2 hours. Dichloromethane and NH ₄ Cl solution were added. The organic phase was separated, washed with NH ₄ Cl solution, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (DCM / MeOH) to give the title compound. Brown powder.

30a: N- (4-fluoro-benzylaminyl)-{9-[(2R) 2-deoxy-2-fluoro-2-C-ethynyl-β-D-erythro-furanosyl] -guanine} -5'- Ile-O- (triphenylmethyloxy-tert-butyl-S-acyl-2-thioethyl) phosphate
To a stirred solution of 29 (0.088 mmol) carbon tetrachloride anhydride (880 μL) 4-fluoro-benzylamine (0.44 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours and evaporated to dryness (bath temperature not exceeding 30 ° C.). The crude mixture was filtered through a silica gel plug eluting with a 0-10% methanol gradient in dichloromethane to give the title compound. White solid.

31a: N- (4-fluoro-benzylaminyl)-{9-[(2R) 2-deoxy-2-fluoro-2-C-ethynyl-β-D-erythro-furanosyl] -guanine} -5'- Yl-O- (hydroxy-tert-butyl-S-acyl-2-thioethyl) phosphate
30a (0.09 mmol) was dissolved in dichloromethane (320 μL) and treated with formic acid (32 μL). The mixture is stirred at room temperature for 10 minutes, filtered through a solid phase extraction column eluting with a 0-30% methanol gradient in dichloromethane, and then a reverse phase (C18) silica gel column eluting with a 0-100% acetonitrile gradient in water. Purified by chromatography and lyophilized from a water / dioxane mixture to give the title compound. White solid.

30b: N- (4-methoxy-benzylaminyl- {9-[(2R) 2-deoxy-2-fluoro-2-C-ethynyl-β-D-erythro-furanosyl] -guanine})-5'- Ile-O- (triphenylmethyloxy-tert-butyl-S-acyl-2-thioethyl) phosphate
30b was synthesized from 29 and 4-methoxy-benzylamine as described for 30a. White solid.

31b: N- (4-methoxy-benzylaminyl)-{9-[(2R) 2-deoxy-2-fluoro-2-C-ethynyl-β-D-erythro-furanosyl] -guanine} -5'- Yl-O- (hydroxy-tert-butyl-S-acyl-2-thioethyl) phosphate
31b was synthesized from 30b as described for 31a. White solid.

30c: N- (4-trifluoro-benzylaminyl)-{9-[(2R) 2-deoxy-2-fluoro-2-C-ethynyl-β-D-erythro-furanosyl] -guanine} -5 ′ -Yl-O- (triphenylmethyloxy-tert-butyl-S-acyl-2-thioethyl) phosphate
30c was synthesized from 29 and 4-trifluoromethyl-benzylamine as described for 30a. White solid.

31c: N- (4-trifluoromethyl-benzylaminyl)-{9-[(2R) 2-deoxy-2-fluoro-2-C-ethynyl-β-D-erythro-furanosyl] -guanine} -5 '-Yl-O- (hydroxy-tert-butyl-S-acyl-2-thioethyl) phosphate
31c was synthesized from 30c as described for 31a. White solid.

Additional exemplary compounds synthesized using procedures similar to those described herein are listed below. The names for the compounds synthesized in the examples are described below.
6a: 6-Chloro-9-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] purine
6b: N ² -isobutyryl-9-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] guanine
6c: 1-[(2R) 2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] uracil
6d: 1-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] thymine
6e: N4-benzoyl-1-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] cytosine
6f: 5-Fluoro-1-[(2R) 2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] uracil
6 g: 4-chloro-7-[(2R) 2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] pyrrolo [2,3-d] pyrimidine
7i: 9-[(2R) 2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl (2R)] adenine
7j: 9-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] guanine
7k: 1-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] cytosine
7l: 4-amino-7-[(2R) 2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] pyrrolo [2,3-d] pyrimidine
11c: 1-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] -uracil-5′-yl-bis (S-pivaloyl-2-thio Ethyl phosphate
11l: 1-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] -5-fluorouracil-5′-yl-bis (S-pivaloyl-2 -Thioethyl phosphate)
11k: 1-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] -cytosine-5′-yl-bis (S-pivaloyl-2-thio Ethyl phosphate)
11f: 1-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] -4-aminopyrrolo [2,3-d] pyrimidin-5′-yl -Bis (S-pivaloyl-2-thioethyl phosphate)
16: 9-[(2R) -2,3-dideoxy-2-C-ethynyl-2-fluoro-β-D-glycero-pentofuranosyl] guanine
17: 9-[(2R) -2,3-dideoxy-2-C-ethynyl-2-fluoro-β-D-glycero-pentofuranosyl] guanin-5′-yl-bis (S-pivaloyl-2- Thioethyl phosphate)
20: 9-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] guanin-5′-yl-bis (S-pivaloyl-2-thioethyl) Phosphate
23: 9-[(2R) 2-deoxy-3,5-di-O-isobutyryl-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] guanine
24: N2-isobutyryl-9-[(2R) 2-deoxy-3,5-di-O-isobutyryl-2-C-ethynyl-2-fluoro-β-D-erythropentofuranosyl] guanine
27i: 9-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] adenine 5′-triphosphate sodium salt
27j: 9-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] guanine 5′-triphosphate sodium salt
28: 9-[(2R) -2,3-dideoxy-2-C-ethynyl-2-fluoro-β-D-glycero-pentofuranosyl] guanine 5′-triphosphate sodium salt

3a: 6-chloro-9- [2-oxo-3,5-O- (1,3-diyl-1,1,3,3-tetraisopropyldisiloxane) -β-D-ribo-furanosyl] purine
6-Chloro- [3,5-O- (1,3-diyl-1,1,3,3-tetraisopropyldisiloxane) -β-D-ribo-furanosyl] purine (18.84 mmol) with THF twice Co-evaporated and then dissolved in anhydrous THF (50 mL). DMSO anhydride (119.82 mmol) was added and the resulting solution was cooled between −40 ° C. and −30 ° C. Trifluoroacetic anhydride (36.17 mmol) was added dropwise and the solution was stirred between −40 ° C. and −30 ° C. for 2 hours, followed by EtN ₃ (97.52 mmol). The resulting solution was stirred and allowed to warm to room temperature over 30 minutes, then diluted with diethyl ether, washed with H ₂ O, dried (Na ₂ SO ₄ ) and evaporated to dryness. The crude material was purified by column chromatography eluting with 1% ethyl acetate in dichloromethane. The resulting yellow oil was dissolved in DCM and stirred with excess MgSO ₄ at room temperature for 36 hours, filtered and concentrated under reduced pressure to give the title compound. Light yellow foam.

及び4'a（0.75g、10%）。黄色の油。

4a and 4'a: 6-chloro-9- [3,5-O- (1,3-diyl-1,1,3,3-tetraisopropyldisiloxane) -2-C-trimethysiylethynylethynyl-β -D-arabino-furanosyl] purine (4a) and 6-chloro-9- [3,5-O- (1,3-diyl-1,1,3,3-tetraisopropyl-disiloxane) -2- C-trimethylsilylethynyl-β-D-ribo-furanosyl] purine (4'a)
Trimethylsilylacetylene (59.20 mmol) was dissolved in anhydrous THF (70 mL). n-Butyllithium (37 mL, 1.6 M hexane solution) was added dropwise at -78 ° C. The reaction mixture was stirred at -78 ° C for 30 minutes and then warmed to -55 ° C. A solution of 3a (11.84 mmol) in THF (34 mL) was added dropwise at -78 ° C. The reaction mixture was stirred at −78 ° C. for 1 hour and then warmed to −30 ° C. The reaction was quenched at −78 ° C. by careful addition of saturated aqueous NH ₄ Cl (45 mL). After warming to room temperature, the mixture was diluted with diethyl ether, washed with saturated brine, dried (Na ₂ SO ₄ ) and concentrated to dryness. The crude material was purified by silica gel chromatography eluting with 20% Et ₂ O in petroleum ether to give two compounds: 4a (4.62 g, 62%). Light yellow foam.

And 4'a (0.75 g, 10%). Yellow oil.

5a: 6-chloro-9-[(2R) 2-deoxy-2-fluoro-3,5-O- (1,3-diyl-1,1,3,3-tetraisopropyldisiloxane) -2-C -Trimethylsilylethynyl-β-D-erythro-pentofuranosyl] purine
4a (6.78 mmol) was dissolved in dry toluene (3 1.8 mL) under argon and DAST (40.68 mmol) cooled to −2 ° C. was added dropwise and the cooling bath was removed after complete addition. Stirring was continued for 1.5 hours, the mixture was dissolved in ethyl acetate, poured into saturated NaHCO ₃ and stirred for 5 minutes. The organic layer was washed with saturated brine, dried (Na ₂ SO ₄ ), concentrated and purified by silica gel chromatography eluting with 20% Et ₂ O in petroleum ether to give the title compound (1.11 g, 26%) Got. Yellow oil.

6a: 6-Chloro-9-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] purine
A mixture of 5a (3.65 mmol) and ammonium fluoride (47.45 mmol) in methanol (12.5 mL) was heated at reflux for 2 hours. Upon cooling to room temperature, the mixture was concentrated to dryness and purified by silica gel chromatography eluting with a step gradient of 2-4% methanol in DCM to provide the title compound (0.89 g, 78%). Yellow solid.

7i: 9-[(2R) 2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] adenine
6a (2.24 mmol) was dissolved in saturated ammoniacal methanol (80 mL) and heated in a steel high pressure vessel at 90 ° C. for 4 hours. After cooling to room temperature, the mixture was coevaporated to dryness and purified by silica gel chromatography eluting with a 5-8% methanol gradient in DCM to give the title compound (305 mg, 46%). Yellow solid.

4b: N ² -isobutyryl-9- [3,5-O- (1,3-diyl-1,1,3,3-tetraisopropyldisiloxane) -2-C-trimethylsilylethynyl-β-D-ribo- Furanosyl] guanine
To a 0 ° C. suspension of CrO ₃ (110.76 mmol) in DCM (220 mL) was added acetic anhydride (110.76 mmol) and pyridine anhydride (221.52 mmol). 9- [3,5-O- (1,3-Diyl-1,1,3,3-tetraisopropyldisiloxane) -arabino-furanosyl] -N ² -isobutyrylguanine (36.92 mmol) in DCM (110 mL The solution in was added dropwise. The cooling bath was removed and the resulting solution was stirred at room temperature for 5 hours. The reaction mixture was poured into cold ethyl acetate, filtered through a silica and celite gel plug, concentrated to dryness and coevaporated twice with toluene. The resulting residue was dissolved in DCM and stirred with excess MgSO ₄ overnight, filtered and evaporated to give the ketone. Trimethylsilylacetylene (88.60 mmol) was dissolved in anhydrous THF (98 mL) under argon. n-Butyllithium (55.4 mL, 1.6 M hexane solution) was added dropwise at -78 ° C. The reaction mixture was stirred at -78 ° C for 30 minutes and then warmed to -55 ° C. A solution of ketone in THF (49 mL) was added dropwise at -78 ° C. The reaction mixture was stirred at -78 ° C for 1 hour, then warmed to -30 ° C and stirred for 3 hours. The reaction was quenched by careful addition of saturated aqueous NH ₄ Cl (72 mL) at −78 ° C. After warming to room temperature, the mixture was diluted with ethyl acetate, washed twice with saturated brine, dried (Na ₂ SO ₄ ) and concentrated to dryness. The crude material was purified using column chromatography eluting with 1.5% MeOH in dichloromethane to give the title compound (8.59 g, 34%, 2 steps). Light yellow foam.

5b: N ² -isobutyryl-9-[(2R) -2-deoxy-2-fluoro-3,5-O- (1,3-diyl-1,1,3,3-tetraisopropyldisiloxane) -2 -C-Trimethyl-silylethynyl-β-D-erythro-pentofuranosyl] guanine
4b (2.89 mmol) was dissolved in dry DCM (60 mL) under argon and pyridine (18.06 mmol) was added. The reaction mixture was cooled to −20 ° C. and DAST (31.35 mmol) was added dropwise. After the addition was complete, the cooling bath was removed. Stirring was continued for 1 hour 15 minutes, the mixture was dissolved in ethyl acetate, poured into saturated NaHCO ₃ and stirred for 5 minutes. The organic layer was washed with saturated brine, dried (Na ₂ SO ₄ ), concentrated and purified by silica gel chromatography eluting with ethyl acetate in DCM (2%) to give the title compound (1.41 g, 70% ) Yellow oil.

6b: N ² -isobutyryl-9-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] guanine
5b (1.89 mmol) was dissolved in methanol (13.8 mL) and ammonium fluoride (24.54 mmol) was added. The resulting solution was stirred at reflux for 1 hour and evaporated to dryness. The crude material was purified by silica gel chromatography eluting with a step gradient of 6-10% methanol in DCM to give the title compound (344 mg, 48%). Pale yellow oil.

7j: 9-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] guanine
6b (1.33 mmol) was dissolved in saturated methanolic ammonia (62 mL) and stirred at room temperature for 20 hours. The reaction mixture was then evaporated to dryness under reduced pressure. The residue was dissolved in water and washed twice with ethyl acetate. The aqueous layer was evaporated and purified by reverse phase column chromatography (C18) eluting with a gradient of 2-15% acetonitrile in water. The resulting residue was then dissolved in hot ethyl acetate, filtered and dried to give the title compound (134 mg, 33%). Yellow solid.

3c: 1- [2-oxo-3,5-O- (1,3-diyl-1,1,3,3-tetraisopropyldisiloxane) -β-D-ribo-furanosyl] uracil
3c was synthesized from 1- [3,5-O- (1,3-diyl-1,1,3,3-tetraisopropyldisiloxane) -ribo-furanosyl] uracil as described for 3a. Light yellow foam.

4c: 1- [3,5-O- (1,3-diyl-1,1,3,3-tetraisopropyldisiloxane) -2-C-trimethylsilylethynyl-β-D-arabino-furanosyl] uracil Yoshimura, Y .; Iino T .; Matsuda, A. Tetrahedron Lett. 1991, 32, 6003-6006.

5c: 1-[(2R) -2-deoxy-2-fluoro-3,5-O- (1,3-diyl-1,1,3,3-tetraisopropyldisiloxane) -2-C-trimethylsilylethynyl -β-D-erythro-pentofuranosyl] uracil
5c was synthesized from 4c as described for 5a. Yellow oil.

6c: 1-[(2R) 2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] uracil
A mixture of 5c (0.56 mmol) and ammonium fluoride (7.31 mmol) was dissolved in methanol (1OmL), stirred at reflux for 1 hour and evaporated to dryness. The resulting residue is purified by silica gel flash column chromatography eluting with a 0-20% methanol gradient in DCM and then with reverse phase column chromatography eluting with a 0-100% acetonitrile gradient in water to give the desired product. This was lyophilized from water (47 mg, 31%). White lyophilized powder.

2d: 1- [3,5-O- (1,3-diyl-1,1,3,3-tetraisopropyldisiloxane) -β-D-ribo-furanosyl] thymine
1- (β-D-ribo-furanosyl) thymine (40.9 mmol) was dissolved in pyridine (435 mL) and the mixture was cooled to 0 ° C. in an ice bath for 25 minutes. TIPSCl ₂ (16.2 mL) was then added and after the addition was complete, the mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 3 hours, diluted with dichloromethane and water and washed with saturated aqueous NaHCO ₃ solution. The organic phases were combined, dried over Na ₂ SO ₄ , filtered and evaporated. The residue was coevaporated with toluene to remove pyridine. The resulting residue was purified by flash column chromatography eluting with a gradient of 0-2% methanol in dichloromethane to give the title compound. Off-white powder.

3d: 1- [2-oxo-3,5-O- (1,3-diyl-1,1,3,3-terolaisopropyldisiloxane) -β-D-ribo-furanosyl] thymine
Acetic anhydride (59 mmol) and pyridine anhydride (120 mmol) were added to a suspension of CrO ₃ (60 mmol) in dichloromethane (200 mL) at 0 ° C. A solution of 2d (20 mmol) in DCM was added dropwise. The cooling bath was removed and the resulting solution was stirred at room temperature for 3 hours. The reaction mixture was poured into cold ethyl acetate, filtered through silica and celite gel plugs, concentrated to dryness and coevaporated twice with toluene to give the title compound. Colorless oil. Molecular formula C ₂₂ H ₃₈ N ₂ O ₇ Si

4d: 1- [3,5-O- (1,3-diyl-1,1,3,3-tetraisopropyldisiloxane) -2-C-trimethylsilylethynyl-β-D-arabino-furanosyl] thymine
4d was synthesized from 3d and trimethylacetylene as described for 4a. Brown solid.

5d: 1-[(2R) -2-deoxy-2-fluoro-3,5-O- (1,3-diyl-1,1,3,3-tetraisopropyldisiloxane) -2-C-trimethyl- Silylethynyl-β-D-erythro-pentofuranosyl] thymine
5d was synthesized from 4a as described for 5a. Brown solid.

6d: 1-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] thymine
6d was synthesized from 5d as described for 7i.

4e: N ⁴ -benzoyl-1- [3,5-O- (1,3-diyl-1,1,3,3-tetraisopropyldisiloxane) -2-C-trimethylsilylethynyl-β-D-arabino- Furanosyl] cytosine
4e was synthesized from 3e and trimethylacetylene as described for 4a. Brown solid.

5e: N ⁴ -benzoyl-1-[(2R) 2-deoxy-2-fluoro-3,5-O- (1,3-diyl-1,1,3,3-tetraisopropyldisiloxane) -2- C-trimethyl-silylethynyl-β-D-erythro-pentofuranosyl] cytosine
5e is N ⁴ -benzoyl-1- [3,5-O- (1,3-diyl-1,1,3,3-tetraisopropyldisiloxane) -2-C-trimethyl-, as described for 5a Synthesis from silylethynyl-D-arabino-furanosyl] cytosine. Yellow solid.

6e: N ⁴ -benzoyl-1-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] cytosine
6e was synthesized from 5e as described for 7i. White powder.

7k: 1-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] cytosine

8k: N ⁴ -dimethoxytrityl-1-[(2R) 2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] cytosine
To a stirred solution of 7k (2.34 mmol) in pyridine (7.2 mL) was added trimethylsilyl chloride (9.36 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. Then 4-dimethylaminopyridine (1.17 mmol) and dimethoxytrityl chloride (3.51 mmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM and saturated NaHCO ₃ solution. The organic phase was washed twice with saturated NaHCO ₃ solution, dried over Na ₂ SO ₄ , filtered and evaporated. The crude material was dissolved in solution NH ₄ OH / dioxin (2: 1) and stirred for 4 hours. The solvent was evaporated and the residue was purified by silica gel chromatography (DCM / EtOH) to give the title compound. White foam.

9k: 1-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] -4-N-dimethoxytrityl-cytosine-5′-yl-bis ( S-Pivaloyl-2-thioethyl phosphate
Add bis (S-pivaloyl-2-thioethyl) N, N-diisopropyl phosphoramidate (0.42 mmol) to a stirred solution in 8k (0.35 mmol) THF anhydride / tetrazole solution (1.05 mmol) at 0 ° C. did. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled to 0 ° C. and tert-butyl hydroperoxide (0.7 mL / mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with DCM and neutralized with saturated Na ₂ S ₂ O ₃ solution. The organic phase was washed twice with H ₂ O, extracted, dried over Na ₂ SO ₄ , filtered and evaporated. The crude material was purified by silica gel chromatography (DCM / EtOH) to give the title compound. Glassy compound.

11k: 1-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] -cytosine-5′-yl-bis (S-pivaloyl-2-thio Ethyl phosphate
9k (34 mmol) was stirred in AcOH / MeOH / H ₂ O (3/6/1) solution for 2 hours and at 50 ° C. for 4 hours. The reaction mixture was then evaporated and purified by silica gel chromatography (DCM / EtOH) to give the title compound. White lyophilized powder.

12: N ² -methoxytrityl-9-[(2R) 2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] guanine
To a stirred solution of 7j (5.18 mmol) in pyridine (7 mL / mmol) was added trimethylsilyl chloride at room temperature. The mixture was stirred at room temperature for 6 hours. Methoxytrityl chloride (6.21 mmol) was then added and the reaction mixture was stirred at room temperature for 16 hours and with NH ₄ OH (4 mL / mmol) for 2 hours. The mixture was diluted with ethyl acetate, washed with H ₂ O, saturated NaHCO ₃ solution, and saturated NaCl solution, dried over Na ₂ SO ₄ , filtered and evaporated. The crude material was purified by silica gel chromatography (DCM / MeOH) to give the title compound. Yellowish oil. Molecular formula C ₃₂ H ₂₈ FN ₅ O ₅ .

13: N ² -methoxytrityl-9-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-5-O-tert-butyldimethylsilyl-β-D-erythro-pentofuranosyl] guanine
To a stirred solution of 12 (2.29 mmol) in pyridine (5 mL) was added tert-butyldimethylsilyl chloride (2.75 mmol) at O ° C. The reaction mixture was stirred at room temperature for 24 hours. This was then diluted in DCM and washed twice with H ₂ O. The organic phase was extracted, dried over Na ₂ SO ₄ , filtered and evaporated. The crude material was purified by silica gel chromatography (DCM / MeOH) to give the title compound. Yellowish oil.

14: N ² -methoxytrityl-9-[(2R) -2,3-dideoxy-2-C-ethynyl-2-fluoro-5-O-tert-butyldimethylsilyl-β-D-glycero-pentofuranosyl Guanine
To a stirred solution of 13 (0.14 mmol) in acetonitrile (47 mL / mmol) was added 4-dimethylaminopyridine (0.56 mmol) and phenylchlorothionoformate (0.43 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. The resulting residue was dissolved in DCM and the organic phase was washed with H ₂ O, HCl (1N), dried over Na ₂ SO ₄ , filtered and evaporated, and co-evaporated with toluene.

The crude material was dissolved in toluene (12 mL / mmol) at room temperature and azo-bis-isobutyronitrile (0.02 mmol) and tributylstannane (0.24 mmol) were added. The reaction mixture was stirred at 125 ° C. for 2 hours and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (DMC / MeOH) to give the title compound. Yellowish oil.

15: N ² -methoxytrityl-9-[(2R) -2,3-dideoxy-2-C-ethynyl-2-fluoro-β-D-glycero-pentofuranosyl] guanine
14 (0.35 mmol) was dissolved in MeOH (20 mL / mmol). Ammonium fluoride (3.55 mmol) was then added at room temperature and the reaction mixture was stirred at 70 ° C. for 2 hours. After concentration under reduced pressure, the crude material was purified by silica gel chromatography (DCM / MeOH) to give the title compound. Beige foam.

16: 9-[(2R) -2,3-dideoxy-2-C-ethynyl-2-fluoro-β-D-glycero-pentofuranosyl] guanine
15 (0.09 mmol) was stirred in AcOH / THF / H ₂ O (3/6/1) solution at 5O ° C. for 1 day. The reaction mixture was then concentrated under reduced pressure and purified by silica gel chromatography, C18 (H ₂ O / ACN). Beige lyophilized powder.

17: 9-[(2R) -2,3-dideoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] -guanin-5′-yl-bis (S-pivaloyl-2 -Thioethyl phosphate)
17 was synthesized from 14 (0.35 mmol) as described for 9. The crude material was then stirred in AcOH / THF / H ₂ O (4/2/1) at 50 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (DCM / MeOH) to give the title compound. Solid beige.

18: N ² -methoxytrityl-9-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-5-O-tert-butyldimethylsilyl-3-O-tetrahydropyranyl-β-D -Erythro-pentofuranosyl] guanine
To a stirred solution of 13 (0.8 mmol) in THF anhydride (20 mL / mmol), p-toluenesulfonic acid (0.12 mmol) and dihydropyran (2 mL / mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 3 days and neutralized with TEA. The mixture was diluted with DCM and washed twice with H ₂ O. The organic phase was dried over Na ₂ SO ₄ , filtered and evaporated. The crude material was purified by silica gel chromatography (DCM / MeOH) to give the title compound.

19: N ² -methoxytrityl-9-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-3-O-tetrahydropyranyl-β-D-erythro-pentofuranosyl] guanine
19 was synthesized from 18 as described for 15. Molecular formula C ₃₇ H ₃₈ FN ₅ O ₆ . Scan ES ⁺ 666 (M + H) ⁺ .

21: N ² -tetrahydropyranyl-9-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-5-O-tert-butyldimethylsilyl-3-O-tetrahydropyranyl-β- D-erythro-pentofuranosyl] guanine
21 was obtained from 18 purifications. Molecular formula C ₂₈ H ₄₂ FN ₅ O ₆ Si. Scan ES ⁺ 592 (M + H) ⁺ , UV λ _max 273 nm.

22: N ² -tetrahydropyranyl-9-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-3-O-tetrahydropyranyl-β-D-erythro-pentofuranosyl] guanine
22 was synthesized from 21 (0.46 mmol) as described for 15. Molecular formula C ₂₂ H ₂₈ FN ₅ O ₆ .

20: 9-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] guanin-5′-yl-bis (S-pivaloyl-2-thioethyl) Phosphate
20 was synthesized from 19 (0.09 mmol) as described for 9k. The crude material was then stirred overnight in AcOH / THF / H ₂ O (4/2/1) solution at room temperature. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (DCM / MeOH) to yield the title compound. White lyophilized powder.

25: 1-[(2R) -2-deoxy-2-fluoro-3,5-O- (1,3-diyl-1,1,3,3-tetraisopropyldisiloxane) -2-C-trimethylsilylethynyl -β-D-erythro-pentofuranosyl] -4-thiouracil
5c (820 mg, 1.40 mmol) was dissolved in 1,2-dichloroethane anhydride (35 mL) and treated with Lawesson reagent (1.13 g, 2.80 mmol). The reaction mixture was stirred at reflux overnight and evaporated to dryness. The resulting residue was filtered through a silica gel plug eluting with a gradient of 0-5% ethyl acetate in dichloromethane to give the title compound. Yellow oil. Molecular formula _{C 26 H 45 FN 2 O 5} SSi 3 LR LC / MS:.. (M + H +) 601.3 (MH -) 599.3 (7.03 min) UV λ max 332 nm R / 0.71 (Ethyl acetate / CH2Cl, 7 / 93, v / v).

26: 1-[(2R) 2-deoxy-2-fluoro-3,5-O- (1,3-diyl-1,1,3,3-tetraisopropyldisiloxane) -2-C-ethynyl-β -D-erythro-pentofuranosyl] cytosine Crude 25 was dissolved in saturated ammonia in methanol (9 mL). The resulting solution was heated by microwave at 120 ° C. for 20 minutes and concentrated under reduced pressure to give the title compound. Oily residue. Molecular formula C ₂₆ H ₄₆ FN ₃ O ₅ Si ₃ LR LC / MS (B): (M + H ⁺ ) 512.3 (MH ⁻ ) 510.3 (5.33 min). UV λ _max1 242 nm, λ _max2 273 nm.

27i: 9-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] adenine 5′-triphosphate sodium salt
To a solution of 7i (0.286 mmol) in triethyl phosphate (750 μL) was added phosphoryl chloride (75 μL, 0.807 mmol) at 0 ° C. The reaction mixture A was stirred at 5 ° C. overnight. Tributylammonium pyrophosphate (PPi / Bu ₃ N 1/1, 5, 1 g, 2.19 mmol) was dissolved in DMF anhydride (2 mL). Tributylamine (420 μL, 1.76 mmol) was added to PPi and the resulting mixture was stirred at 0 ° C. for 15 minutes. 2.4 mL of this solution was added to reaction mixture A. The reaction mixture was stirred at 0 ° C. for 1 minute. The reaction was carefully quenched with TEAB 1M (pH = 7,5, 10 mL), stirred at 0 ° C. for 20 minutes, then diluted with water and ethyl acetate. The aqueous phase was concentrated under reduced pressure. The crude material was subjected to DEAE-Sephadex chromatography eluting with a gradient of 10 ⁻³ M TEAB. The desired fractions were combined, concentrated under reduced pressure, coevaporated with a water / methanol mixture and finally coevaporated with water. The resulting residue was purified by semi-preparative HPLC. Fractions containing the expected product were concentrated under reduced pressure, co-evaporated with a water / methanol mixture and lyophilized from water. Triethylammonium salt triphosphate was eluted with water three times from a Dowex Na + resin column, and lyophilized from water to obtain a sodium salt.

27i: 9-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] guanine 5′-triphosphate sodium salt
27j was synthesized from 7j as described for 27.

2 g: 4-chloro-7- [3,5-O- (1,3-diyl-1,1,3,3-tetraisopropyldisiloxane) -β-D-ribo-furanosyl] pyrrolo [2,3- d] Pyrimidine
2g was synthesized from 9- [β-D-ribo-furanosyl] -7-deaza-6-chloropurine as described for Intermediate 12. Yellow oil.

3 g: 4-chloro-7- [2-oxo-3,5-O- (1,3-diyl-1,1,3,3-tetraisopropyldisiloxane) -β-D-erythro-pentofuranosyl] Pyrrolo [2,3-d] pyrimidine
3g was synthesized from 2g as described in 3d. Brown solid. Molecular formula C ₂₃ H ₃₆ ClN ₃ O ₅ Si ₂ . Scan ES ⁺ (M + H) ⁺ 528, UV λmax 271 nm.

4 g: 4-chloro- [3,5-O- (1,3-diyl-1,1,3,3-tetraisopropyldisiloxane) -2-C-trimethylsilylethynyl-β-D-arabino-furanosyl] pyrrolo [2,3-d] pyrimidine
4g was synthesized from 3g as described for 4a. Beige solid.

5 g: 4-chloro-7-[(2R) 2-deoxy-2-fluoro-3,5-O- (1,3-diyl-1,1,3,3-tetraisopropyldisiloxane) -2-C -Trimethylsilylethynyl-β-D-erythro-pentofuranosyl] pyrrolo [2,3-d] pyrimidine
5g was synthesized from 4g as described for 5a. Yellow oil.

6 g: 4-chloro-7-[(2R) 2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] pyrrolo [2,3-d] pyrimidine
6g was synthesized from 5g as described for 6a. Yellow oil.

7l: 4-amino-7-[(2R) 2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] pyrrolo [2,3-d] pyrimidine
7l was synthesized from 6g as described for 6a. White lyophilized powder.

23: 9-[(2R) 2-deoxy-3,5-di-O-isobutyryl-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] guanine
9-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-furanosyl] guanine (0.16 mmol), 4-dimethylaminopyridine (0.01 mmol), triethylamine (0.48 mmol) , And a solution of isobutyric anhydride (0.48 mmol) in acetonitrile (1 mL) was stirred at room temperature for 6 hours. The reaction mixture was hydrolyzed with saturated NaHCO ₃ solution. Ethyl acetate was added. The organic phase was separated, washed with NaCl saturated solution, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (DCM / EtOH) to give the title compound. White powder.

24: N-2-isobutyryl-9-[(2R) 2-deoxy-3,5-di-O-isobutyryl-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] guanine
24 was obtained from 23 purifications. White powder.

4f: 5-fluoro-1- [3,5-O- (1,3-diyl-1,1,3,3-tetraisopropyldisiloxane) -2-C-trimethylsilylethynyl-β-D-arabino-furanosyl ] Uracil
4f was synthesized from 3f as described for 4a. Orange solid.

5f: 5-fluoro-1-[(2R) -2-deoxy-2-fluoro-3,5-O- (1,3-diyl-1,1,3,3-tetraisopropyldisiloxane) -2- C-trimethyl-silylethynyl-β-D-erythro-pentofuranosyl] uracil
5f was synthesized from 4f as described for 5a. White solid.

6f: 5-Fluoro-1-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] uracil
6f was synthesized from 5f as described for 6a. White solid.

11f: 1-[(2R) -2-deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-pentofuranosyl] -5-fluorouracil-5′-yl-bis (S-pivaloyl-2 -Thioethyl phosphate)
11f was synthesized from 6f as described in 9k. White solid.

28: 9-[(2R) -2,3-dideoxy-2-C-ethynyl-2-fluoro-β-D-glycero-pentofuranosyl] guanine (5′-triphosphate sodium 28) describes 27i As synthesized, synthesized from 16. White powder.

  All publications, patents, and patent applications cited herein are hereby incorporated into this specification as if the individual publications or patent applications were specifically and individually indicated to be incorporated by reference. Incorporated by reference. Although the claimed subject matter has been described in terms of various embodiments, those skilled in the art will recognize that various modifications, substitutions, omissions and changes may be made without departing from the spirit thereof. . Accordingly, it is intended that the scope of the subject matter be limited only by the scope of the following claims and the equivalents thereof.

Claims (54)

formula:

Or a pharmaceutically acceptable salt, stereoisomeric form, tautomeric form, or polymorphic form of the formula
R ^y is an optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, hydroxyalkyl, amino, heterocyclyl, or heteroaryl;
R ^a and R ^b are selected as follows:
i) R ^a and R ^b are each independently hydrogen or optionally substituted alkyl, carboxyalkyl, hydroxyalkyl, hydroxyarylalkyl, acyloxyalkyl, aminocarbonylalkyl, alkoxycarbonylalkyl, aryl, arylalkyl, Is cycloalkyl, heteroaryl, or heterocyclyl; or
ii) R ^a and R ^b together with the nitrogen atom to which they are substituted form a 3-7 membered heterocyclic or heteroaryl ring; and
R ¹ is a moiety that can be derived by removal of hydrogen from the hydroxy group of the antiviral agent;
Also optionally, when R ^y is tert-butyl or hydroxy-tert-butyl, R ¹ is not 3′-azido-2 ′, 3′-dideoxythymidine. ). formula:

Or a pharmaceutically acceptable salt, stereoisomeric form, tautomeric form, or polymorphic form thereof. formula:

Or a pharmaceutically acceptable salt, stereoisomeric form, tautomeric form, or polymorphic form thereof. formula:

Or a pharmaceutically acceptable salt, stereoisomeric form, tautomeric form, or polymorphic form thereof. formula:

Having a compound of claim 1, or a pharmaceutically acceptable salt, stereoisomeric forms, tautomeric forms, or polymorphic forms (wherein, R ^2, and R ³ is H independently Or R ² and R ³ are linked to form a cyclic group by an alkyl, ester, or carbamate bond. formula:

Or a pharmaceutically acceptable salt, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein R ^d is hydrogen, methyl, or methoxy;
Each R ^L is independently H, carbamyl, linear, branched, or cyclic alkyl; acyl; CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted Aryl, sulfonate ester, lipid, amino acid; amino acid residue; or carbohydrate. ). formula:

Or a pharmaceutically acceptable salt, stereoisomeric form, tautomeric form, or polymorphic form thereof. ^{7.R 1} is a substituted alkyl and R ^a and R ^b are independently hydrogen, alkyl, substituted alkyl, benzyl, or substituted benzyl. The described compound. 8. The compound according to claim 7, wherein ^Ry is hydroxyalkyl or aminoalkyl. R ^y is —OR ^c , —C (R ^c ) ₃ , or NHR ^c —, wherein each R ^c is independently alkyl, substituted alkyl, aryl, or substituted aryl; 10. The compound according to any one of claims 1 to 9, wherein R ^a and R ^b are independently hydrogen, alkyl, substituted alkyl, benzyl, or substituted benzyl. 11. A compound according to any one of claims 1 to 10, wherein R ^a and R ^b are independently hydrogen, benzyl, or substituted alkyl. R ^y is selected from the group consisting of alkyl and hydroxyalkyl, any one compound according to claims 1-11. R ^y is -C (CH ₃₎ there ₂ CH ₂ OH, compounds according to any of claims 1 to 12. R ² and R ³ are each hydrogen, R ^a is hydrogen, R ^b is benzyl, and R ^y is -C (CH ₃ ) ₂ CH ₂ OH. A compound according to any one. R ¹ is ribavirin, viramidine, valopicitabine, is selected from the PSI-6130, and MK-0608, a compound according to claim 1. The compound according to claim 1, wherein R ¹ is selected from resiquimod or sergosivir. The compound of claim 1, wherein R ¹ is selected from lamivudine, entecavir, terbivudine, rasivil, emtricitabine, clevudine, amadoxovir, bartolucitabine, tenofovir, and adefovir. The compound of claim 1 selected from:

. The compound of claim 1 having the following structure:

.   A method for the treatment of a host infected with a flaviviridae virus or hepatitis B virus, comprising an effective therapeutic amount of a compound according to any one of claims 1, 2, 3, 4, or 5. Said method comprising administering.   21. The method of claim 20, wherein the virus is hepatitis C.   24. The method of claim 21, wherein the host is a human. The compound is

23. The method according to claim 21, which is a pharmaceutically acceptable salt or stereoisomer thereof.   23. The method of claim 21, wherein said administration indicates to said liver of said host an equivalent amount of said compound, or a pharmaceutically acceptable salt, or stereoisomer thereof.   The compound, or a pharmaceutically acceptable salt or stereoisomer thereof is interferon, ribavirin, interleukin, NS3 protease inhibitor, cysteine protease inhibitor, phenanthrenequinone, thiazolidine derivative, thiazolidine, benzanilide, helicase inhibitor, polymerase In combination with a second antiviral agent optionally selected from the group consisting of inhibitors, nucleotide analogs, gliotoxin, cerulenin, antisense phosphorothioate oligodeoxynucleotides, inhibitors of IRES-dependent translation, and ribozymes 23. The method of claim 21, wherein the methods are administered alternately.   The compound, or a pharmaceutically acceptable salt or stereoisomer thereof is interferon, ribavirin, interleukin, NS3 protease inhibitor, cysteine protease inhibitor, phenanthrenequinone, thiazolidine derivative, thiazolidine, benzanilide, helicase inhibitor, polymerase In combination with a second antiviral agent optionally selected from the group consisting of inhibitors, nucleotide analogs, gliotoxin, cerulenin, antisense phosphorothioate oligodeoxynucleotides, inhibitors of IRES-dependent translation, and ribozymes 25. The method of claim 24, wherein the methods are administered in alternation or alternation.   The second agent is pegylated interferon α2a, interferon alphacon-1, natural interferon, albuferon, interferon β-1a, omega interferon, interferon α, interferon γ, interferon τ, interferon δ, and interferon γ 27. The method of claim 26, wherein the method is selected from the group consisting of -1b.   25. The method of claim 24, wherein the host is a human.   30. The method of claim 28, wherein the administration directs a substantial amount of the compound, or a pharmaceutically acceptable salt, or stereoisomer thereof to the liver of the host.   21. The method of claim 20, comprising treating a human host infected with hepatitis B virus. The compound is

And
In which R ^y is hydroxyalkyl and optionally —C (CH ₃ ) ₂ CH ₂ OH;
Wherein R ^a and R ^b are independently hydrogen, alkyl, substituted alkyl, benzyl, or substituted benzyl; and
Optionally, the compound is

And
Optionally, the compound, or a pharmaceutically acceptable salt thereof, is from interferon α-2b, peginterferon α-2a, lamivudine, entecavir, terbivudine, rasivil, emtricitabine, clevudine, amdoxovir, bartolucitabine, tenofovir, and adefovir 32. The method of claim 30, wherein the method is administered in combination or alternation with an optional second antiviral agent.   32. The method of claim 31, wherein the administration directs a substantial amount of the compound, or a pharmaceutically acceptable salt thereof, to the liver of the host.   A method of treating hepatitis C or hepatitis B infection, wherein a nucleoside or a nucleoside analog phosphoramidate or phosphonoamidate derivative, or a pharmaceutically acceptable salt or stereoisomer thereof is obtained in an individual in need thereof. Administering the therapeutically effective amount of the body.   A pharmaceutical composition comprising a compound of any one of claims 1, 2, 3, 4, or 5 and a pharmaceutically acceptable excipient, carrier, or diluent. The compound is

35. The composition of claim 34, wherein the composition is a pharmaceutically acceptable salt or stereoisomer thereof. The compound is

35. The composition of claim 34, or a pharmaceutically acceptable salt or stereoisomer thereof.   35. The composition of claim 34, wherein the composition is an oral formulation.   40. The composition of claim 36, wherein the composition is an oral formulation.   Use of a compound according to any one of claims 1, 2, 3, 4 or 5 for the treatment of a host infected with a flaviviridae virus or hepatitis B virus.   40. Use according to claim 39, wherein the virus is hepatitis C.   41. Use according to claim 40, wherein the host is a human. The compound is

40. The use according to claim 39, which is or a pharmaceutically acceptable salt or stereoisomer thereof.   40. The use of claim 39, wherein a substantial amount of the compound, or a pharmaceutically acceptable salt, or stereoisomer thereof is directed to the host liver.   The compound, or a pharmaceutically acceptable salt or stereoisomer thereof is interferon, ribavirin, interleukin, NS3 protease inhibitor, cysteine protease inhibitor, phenanthrenequinone, thiazolidine derivative, thiazolidine, benzanilide, helicase inhibitor, polymerase In combination with a second antiviral agent optionally selected from the group consisting of an inhibitor, a nucleotide analog, gliotoxin, cerulenin, an antisense phosphorothioate oligodeoxynucleotide, an IRES-dependent translation inhibitor, and a ribozyme, 40. Use according to claim 39, or alternatively administered.   The compound, or a pharmaceutically acceptable salt or stereoisomer thereof is interferon, ribavirin, interleukin, NS3 protease inhibitor, cysteine protease inhibitor, phenanthrenequinone, thiazolidine derivative, thiazolidine, benzanilide, helicase inhibitor, polymerase In combination with or alternating with a second antiviral agent selected from the group consisting of an inhibitor, a nucleotide analog, gliotoxin, cerulenin, an antisense phosphorothioate oligodeoxynucleotide, an IRES-dependent translation inhibitor, and a ribozyme 45. Use according to claim 44, wherein   The second agent is pegylated interferon α2a, interferon alphacon-1, natural interferon, albuferon, interferon β-1a, omega interferon, interferon α, interferon γ, interferon τ, interferon δ, and interferon γ 46. Use according to claim 45, selected from the group consisting of -1b.   44. Use according to claim 43, wherein the host is a human.   48. Use according to claim 47, wherein the administration directs a substantial amount of the compound, or a pharmaceutically acceptable salt, or stereoisomer thereof to the liver of the host.   40. Use according to claim 39, wherein the treatment comprises administering the compound to a human host infected with hepatitis B virus.   The compound, or a pharmaceutically acceptable salt thereof, is optionally selected from interferon α-2b, pegylated interferon α-2a, lamivudine, entecavir, terbivudine, rasibil, emtricitabine, clevudine, amdoxovir, bartolucitabine, tenofovir, and adefovir 50. Use according to claim 49, wherein the second antiviral agent is administered in combination or alternation.   51. Use according to claim 50, wherein a substantial amount of the compound, or a pharmaceutically acceptable salt thereof, is directed to the host liver.   Use of a nucleoside or nucleoside analogue phosphoramidate or phosphonoamidate derivative, or a pharmaceutically acceptable salt or stereoisomer thereof, for the treatment of hepatitis C or hepatitis B infection.   20. Use of a compound according to any one of claims 1 to 19 for the preparation of a medicament for the treatment of a host infected with flaviviridae virus or hepatitis B virus.   54. Use according to claim 53, wherein the virus is hepatitis C.

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